Autotaxin inhibitors

ABSTRACT

The present invention relates to compounds according to formula (I) as autotaxin inhibitors and the use of such compounds for the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, which are caused, mediated and/or propagated by increased lysophosphatic acid levels and/or the activation of autotaxin, in particular of different cancers.

TECHNICAL FIELD

The present invention relates to compounds as autotaxin inhibitors andthe use of such compounds for the treatment and/or prophylaxis ofphysiological and/or pathophysiological conditions, which are caused,mediated and/or propagated by increased lysophosphatic acid levelsand/or the activation of autotaxin, in particular of different cancers.

PRIOR ART

Autotaxin (ATX) is the enzyme apparently responsible for increasedlysophosphatidic acid (LPA) levels in ascites and plasma of ovariancancer patients (Xu et al., Clinical Cancer Research 1995, 1: 1223; Xuet al., Biochem. J. 1995, 309: 933), because it transformslysophatidylcholine (LPC) to LPA (Tokumura et al., J. Biol. Chem. 2002,277: 39436; Umezu-Gozo et al., J. Biol. Chem. 2002, 158: 227).

LPA is an intracellular lipid mediator, which influences a multiplicityof biologic and biochemical processes such as smooth muscle contraction,thrombocyte aggregation and apoptosis (Tigyi et al., Prog. Lipid Res.2003, 42: 498; Mills et al., Nat. Rev. Cancer 2003, 3: 582; Lynch et al.Prost. Lipid Med. 2001, 64: 33). Furthermore, LPA is found in increasedconcentrations in plasma and ascites fluid of ovarian cancer patients ofearly and late phase.

LPA has been shown to promote tumor cell proliferation, survival,migration and invasion into neighboring tissues, which can result in theformation of metastases (Xu et al., Clinical Cancer Research 1995, 1:1223; Xu et al., Biochem. J. 1995, 309: 933). These biological andpathobiological processes are switched on through the activation ofG-protein coupled receptors by LPA (Contos et al., Mol. Pharm. 2000, 58:1188).

Increased levels of LPA, altered receptor expression and alteredresponses to LPA may contribute to the initiation, progression oroutcome of ovarian cancer. Furthermore, LPA is potentially also involvedin prostate, breast, melanoma, head and neck, bowel and thyroid cancers.

For all these reasons in the course of treating tumor patients it isdesirable to lower the LPA level. This can be achieved through theinhibition of enzymes which are involved in LPA biosynthesis, such asATX (Sano et al., J. Biol. Chem. 2002, 277: 21197; Aoki et al., J. Biol.Chem. 2003, 277: 48737).

ATX belongs to the family of nucleotide pyrophosphatases andphosphodiesterases (Goding et al., Immunol. Rev. 1998, 161: 11). Itrepresents an important starting point for anti-tumor therapy (Mills etal. Nat. Rev. Cancer 2003, 3: 582; Goto et al. J. Cell. Biochem. 2004,92: 1115), since it is increasingly expressed in tumors and effectstumor cell proliferation and invasion into neighboring tissues both ofwhich can lead to the formation of metastases (Nam et al. 2000,Oncogene, Vol. 19 Seite 241). In addition, in the course of angiogenesisATX together with other anti-angiogenetic factors brings about bloodvessel formation (Nam et al. Cancer Res. 2001, 61: 6938). Angiogenesisis an important process during tumor growth as it secures supply of thetumor with nutrients. Therefore, the inhibition of angiogenesis is animportant starting point of cancer and tumor therapy, by means of whichthe tumor is to be starved (Folkman, Nature Reviews Drug Discovery 2007,6: 273-286).

Mutagenesis studies suggest an essential function of the PDE domain ofATX for LPA generation. Though this particular PDE domain shares littlehomology with other known PDEs, it is considered to be druggable byNCEs.

No severe adverse effects are expected for the inhibition of ATX as LPAinvolved in wound healing in this context is produced by anotherpathway.

Since ATX is a relatively novel target, the amount of preclinical dataon protein production, in vitro and in vivo assays is rather limited. Notarget-dependent cell model has been described but LPA itself is anexcellent biomarker to follow ATX inhibition in vitro and in vivo.Neither structural information nor reference compounds are available.

Compounds that are capable of inhibiting ATX are described in Peng etal. (Bioorganic & Medicinal Chemistry Letters 2007, 17: 1634-1640). Thethere described compounds represent lipid analogues, which structurallyshare no similarities with the compounds of the present invention.

Further prior art documents are as follows:

DE 19834751 relates to heterobicyclic substituted (hetero)aromaticamidines or nitriles as thrombin inhibitors, antithrombotic agents orintermediates. The patent application does not mention the inhibition ofautotaxin.

WO 99/24035 discloses benzothiazolecarboxamides as protein tyrosinekinase inhibitors. The patent application does not mention theinhibition of autotaxin.

WO 2002/102380 describes monocyclic or bicyclic carbocycles andheterocycles as factor Xa inhibitors. The patent application does notmention the inhibition of autotaxin.

WO 2003/097615 is directed to treatment of fibroproliferative diseases,such as diabetic neuropathy, involving identifying a non-peptide smallmolecule, selectively binding to a transforming growth factor betakinase receptor and administering the molecule to subjects. The patentapplication does not mention the inhibition of autotaxin.

US 2003/0139431 relates to the use of quinazoline- andquinolino-guanidine derivatives for treating urge incontinence, pain,memory disorders, endocrine disorders, psychotic behaviour, diabetes,hypertension and gastrointestinal disorders. The patent application doesnot mention the inhibition of autotaxin.

WO 2004/099192 describes heterocycle substituted carboxylic acids whichcan be used in the treatment of metabolic disorders. The patentapplication does not mention the inhibition of autotaxin.

WO 2005/003100 deals with the use of quinazoline derivatives for thetreatment of tubulin inhibitor mediated diseases, such as cancer,autoimmune diseases, autoimmune lymphoproliferative syndrome,inflammation and viral infections. The patent application does notmention the inhibition of autotaxin.

WO 2005/023761 is directed to cytokine inhibitors that are useful fortreating rheumatoid arthritis and ulcerative colitis. The patentapplication does not mention the inhibition of autotaxin.

WO 2006/062972 discloses heterocyclic compounds that function asselective inhibitors of serine protease enzymes of the coagulationcascade and can be used for the treatment of arterial cardiovascularthromboembolic disorders, thromboembolic disorders, unstable angina andacute coronary syndrome. The patent application does not mention theinhibition of autotaxin.

WO 2006/066879 relates to benzo-heterocyclic compounds as voltage-gatedpotassium channel modulators. The patent application does not mentionthe inhibition of autotaxin.

WO 2006/072828 is directed to heteroaromatic quinoline compounds thatserve as PDE inhibitors, in particular PDE10 inhibitors. These compoundscan be used for the treatment of central nervous system disorders, suchas psychotic disorders, anxiety disorders, movement disorders, mooddisorders and neurodegenerative disorders. The patent application doesnot mention the inhibition of autotaxin.

WO 2006/074147 describes 4-arylamino-quinazoline as caspase-3 cascadeactivators that can be used for the treatment of cancer, autoimmunediseases, autoimmune lymphoproliferative syndrome, synovial cellhyperplasia, inflammation and viral infections. The patent applicationdoes not mention the inhibition of autotaxin.

WO 2006/099379 discloses benzoimidazole, benzooxazole and benzothiazolederivatives as betasecretase inhibitors. The patent application does notmention the inhibition of autotaxin.

WO 2006/108107 deals with diarylamine derivatives that are steroidhormone nuclear receptor modulators and can be used for the treatment ofhypokalemia, hypertension, congestive heart failure, renal failure,artherosclerosis and obesity. The patent application does not mentionthe inhibition of autotaxin.

WO 2007/030582 relates to alkyl amine acompounds as potassium channel 1function inhibitors that are useful for the treatment of arrhythmia,atrial fibrillation, atrial flutter, supraventricular arrhythmias,gastrointestinal disorders, esophagitis and asthma. The patentapplication does not mention the inhibition of autotaxin.

WO 2007/076034 describes fused bicyclic arene compounds that function ashepatitis C virus replication inhibitors and can be used for thetreatment hepatitis C or other viral infections. The patent applicationdoes not mention the inhibition of autotaxin.

WO 2007/110868 discloses novel heterocyclic compounds that exhibit adopamine receptor, preferably D4 receptor, antagonistic activity and/ora PDE5 inhibitory activity. These compounds can be used for thetreatment of descreased libido, orgasm disorder and erectiledysfunction. The patent application does not mention the inhibition ofautotaxin.

WO 2008/038051 is directed to heterocyclic compounds for the treatmentof inflammatory or immunological diseases, such as cystic fibrosis. Thepatent application does not mention the inhibition of autotaxin.

WO 2008/038053 deals with heterocyclic compounds as voltage-dependentpotassium channel inhibitors. The patent application does not mentionthe inhibition of autotaxin.

WO 2008/060621 is directed to aminopyrrolidines as chemokine receptorantagonists. The patent application does not mention the inhibition ofautotaxin.

WO 2008/091580 relates to fungicidal amides and methods for controllingplant diseases caused by a fungal pathogen. The patent application doesnot mention the inhibition of autotaxin.

The citation of any reference in this application is not an admissionthat the reference is relevant prior art to this application.

DESCRIPTION OF THE INVENTION

The present invention has the object to provide novel autotaxininhibitors.

The object of the present invention has surprisingly been solved in oneaspect by providing a compound according to formula (I)

wherein:

-   -   W₁, W₂ together independently form “—N═N—, —C(O)—O—, —C(O)—S—,        —C(O)—N(R5)-, —C(O)—C(R6)(R7)-, —N═C[N(R8)(R9)]—”;    -   Y₁ is independently selected from the group consisting of        “—C(O)—, —C(S)—, —N(R10)-C(O)—, —C(O)—N(R11)-, —C(R12)(R13)-,        single bond”;    -   Y₂ is independently selected from the group consisting of        “—C(R14)(R15)-, —O—, —N(R16)-, —C(O)—NH—, single bond”;    -   Z₁ is independently selected from the group consisting of “O, S,        N(R17)”;    -   L is independently selected from the group consisting of the        group consisting of:

-   -   B is independently selected from the group consisting of        “cycloalkyl, heterocyclyl, aryl, heteroaryl”, wherein        “cycloalkyl, heterocyclyl, aryl, heteroaryl” can be        independently substituted with one or more identical or        different substituents selected from the group consisting of:        “(i) “hydrogen, alkyl, (C₉-C₃₀)alkyl, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, halogen, —F, —Cl, —Br,        —I, —CN, —CF₃, —N₃, —NH₂, —NHX1, —NX2X3, —NO₂, —OH, —OCF₃,        —SCF₃, —SH, —O—SO₃H, —OP(O)(OH)₂, —CHO, —COOH, —C(O)NH₂, —SO₃H,        —P(O)(OH)₂, —C(O)—X4, —C(O)O—X5, —C(O)NH—X6, —C(O)NX7X8, —O—X9,        —O(—X10-O)_(a)—H (a=1, 2, 3, 4, 5), —O(—X11-O)_(b)—X12 (b=1, 2,        3, 4, 5), —OC(O)—X13, —OC(O)—O—X14, —OC(O)—NHX15,        —O—C(O)—NX16X17, —OP(O)(OX18)(OX19), —OSi(X20)(X21)(X22),        —OS(O₂)—X23, —NHC(O)—NH₂, —NHC(O)—X24, —NX25C(O)—X26,        —NH—C(O)—O—X27, —NH—C(O)—NH—X28, —NH—C(O)—NX29X30,        —NX31-C(O)—O—X32, —NX33-C(O)—NH—X34, —NX35-C(O)—NX36X37,        —NHS(O₂)—X38, —NX39S(O₂)—X40, —S—X41, —S(O)—X42, —S(O₂)—X43,        —S(O₂)NH—X44, —S(O₂)NX45X46, —S(O₂)O—X47, —P(O)(OX48)(OX49),        —Si(X50)(X51)(X52), —C(NH)—NH₂, —C(NX53)-NH₂, —C(NH)—NHX54,        —C(NH)—NX55X56, —C(NX57)-NHX58, —C(NX59)-NX60X61,        —NH—C(O)—NH—O—X62, —NH—C(O)—NX63-O—X64, —NX65-C(O)—NX66-O—X67,        —N(—C(O)—NH—O—X68)₂, —N(—C(O)—NX69-O—X70)₂,        —N(—C(O)—NH—O—X71)(—C(O)—NX72-O—X73), —C(S)—X74, —C(S)—O—X75,        —C(S)—NH—X76, —C(S)—NX77X78, —C(O)—NH—O—X79, —C(O)—NX80-O—X81,        —C(S)—NH—O—X82, —C(S)—NX83-O—X84, —C(O)—NH—NH—X85,        —C(O)—NH—NX86X87, —C(O)—NX88-NX89X90, —C(S)—NH—NH—X91,        —C(S)—NH—NX92X93, —C(S)—NX94-NX95X96, —C(O)—C(O)—O—X97,        —C(O)—C(O)—NH₂, —C(O)—C(O)—NHX98, —C(O)—C(O)—NX99X100,        —C(S)—C(O)—O—X101, —C(O)—C(S)—O—X102, —C(S)—C(S)—O—X103,        —C(S)—C(O)—NH₂, —C(S)—C(O)—NHX104, —C(S)—C(O)—NX105X106,        —C(S)—C(S)—NH₂, —C(S)—C(S)—NHX107, —C(S)—C(S)—NX108X109,        —C(O)—C(S)—NH₂, —C(O)—C(S)—NHX110, —C(O)—C(S)—NX111X112”;        -   wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12,            X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24,            X25, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36,            X37, X38, X39, X40, X41, X42, X43, X44, X45, X46, X47, X48,            X49, X50, X51, X52, X53, X54, X55, X56, X57, X58, X59, X60,            X61, X62, X63, X64, X65, X66, X67, X68, X69, X70, X71, X72,            X73, X74, X75, X76, X77, X78, X79, X80, X81, X82, X83, X84,            X85, X86, X87, X88, X89, X90, X91, X92, X93, X94, X95, X96,            X97, X98, X99, X100, X101, X102, X103, X104, X105, X106,            X107, X108, X109, X110, X111, X112 are independently from            each other selected from the group consisting of:        -   “alkyl, (C₉-C₃₀)alkyl, cycloalkyl, cycloalkylalkyl,            heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,            heteroaryl, heteroarylalkyl” and        -   wherein alternatively X7, X8 and/or X16, X17 and/or X29, X30            and/or X36, X37 and/or X45, X46 and/or X55, X56 and/or X60,            X61 and/or X77, X78 and/or X86, X87 and/or X89, X90 and/or            X92, X93 and/or X95, X96 and/or X99, X100 and/or X105, X106            and/or X108, X109 and/or X111, X112 respectively together            can also form “heterocyclyl”;        -   wherein optionally above substituents of substituents            group (i) can in turn independently from each other be            substituted with one or more identical or different            substituents V;    -   R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14,        R15, R16, R17 are independently from each other selected from        the group consisting of: “V”;    -   V is independently selected from the group consisting of: “(i)        “hydrogen, alkyl, (C₉-C₃₀)alkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, halogen, —F, —Cl, —Br, —I, —CN, —CF₃, —N₃,        —NH₂, —NHA1, —NA2A3, —NO₂, —OH, —OCF₃, —SCF₃, —SH, —O—SO₃H,        —OP(O)(OH)₂, —CHO, —COOH, —C(O)NH₂, —SO₃H, —P(O)(OH)₂, —C(O)-A4,        —C(O)O-A5, —C(O)NH-A6, —C(O)NA7A8, —O-A9, —O(-A10-O)_(a)—H (a=1,        2, 3, 4, 5), —O(-A11-O)_(b)-A12 (b=1, 2, 3, 4, 5), —OC(O)-A13,        —OC(O)—O-A14, —OC(O)—NHA15, —O—C(O)—NA16A17, —OP(O)(OA18)(OA19),        —OSi(A20)(A21)(A22), —OS(O₂)-A23, —NHC(O)—NH₂, —NHC(O)-A24,        —NA25C(O)-A26, —NH—C(O)—O-A27, —NH—C(O)—NH-A28,        —NH—C(O)—NA29A30, —NA31-C(O)—O-A32, —NA33-C(O)—NH-A34,        —NA35-C(O)—NA36A37, —NHS(O₂)-A38, —NA39S(O₂)-A40, —S-A41,        —S(O)-A42, —S(O₂)-A43, —S(O₂)NH-A44, —S(O₂)NA45A46, —S(O₂)O-A47,        —P(O)(OA48)(OA49), —Si(A50)(A51)(A52), —C(NH)—NH₂, —C(NA53)-NH₂,        —C(NH)—NHA54, —C(NH)—NA55A56, —C(NA57)-NHA58, —C(NA59)-NA60A61,        —NH—C(O)—NH—O-A62, —NH—C(O)—NA63-O-A64, —NA65-C(O)—NA66-O-A67,        —N(—C(O)—NH—O-A68)₂, —N(—C(O)—NA69-O-A70)₂,        —N(—C(O)—NH—O-A71)(—C(O)—NA72-O-A73), —C(S)-A74, —C(S)—O-A75,        —C(S)—NH-A76, —C(S)—NA77A78, —C(O)—NH—O-A79, —C(O)—NA80-O-A81,        —C(S)—NH—O-A82, —C(S)—NA83-O-A84, —C(O)—NH—NH-A85,        —C(O)—NH-NA86A87, —C(O)—NA88-NA89A90, —C(S)—NH—NH-A91,        —C(S)—NH-NA92A93, —C(S)—NA94-NA95A96, —C(O)—C(O)—O-A97,        —C(O)—C(O)—NH₂, —C(O)—C(O)—NHA98, —C(O)—C(O)—NA99A100,        —C(S)—C(O)—O-A101, —C(O)—C(S)—O-A102, —C(S)—C(S)—O-A103,        —C(S)—C(O)—NH₂, —C(S)—C(O)—NHA104, —C(S)—C(O)—NA105A106,        —C(S)—C(S)—NH₂, —C(S)—C(S)—NHA107, —C(S)—C(S)—NA108A109,        —C(O)—C(S)—NH₂, —C(O)—C(S)—NHA110, —C(O)—C(S)—NA111A112”;        -   wherein A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12,            A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24,            A25, A26, A27, A28, A29, A30, A31, A32, A33, A34, A35, A36,            A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48,            A49, A50, A51, A52, A53, A54, A55, A56, A57, A58, A59, A60,            A61, A62, A63, A64, A65, A66, A67, A68, A69, A70, A71, A72,            A73, A74, A75, A76, A77, A78, A79, A80, A81, A82, A83, A84,            A85, A86, A87, A88, A89, A90, A91, A92, A93, A94, A95, A96,            A97, A98, A99, A100, A101, A102, A103, A104, A105, A106,            A107, A108, A109, A110, A111, A112 are independently from            each other selected from the group consisting of: “alkyl,            (C₉-C₃₀)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,            heterocyclylalkyl, aryl, arylalkyl, heteroaryl,            heteroarylalkyl” and wherein alternatively A7, A8 and/or            A16, A17 and/or A29, A30 and/or A36, A37 and/or A45, A46            and/or A55, A56 and/or A60, A61 and/or A77, A78 and/or A86,            A87 and/or A89, A90 and/or A92, A93 and/or A95, A96 and/or            A99, A100 and/or A105, A106 and/or A108, A109 and/or A111,            A112 respectively together can also form “heterocyclyl”;        -   wherein optionally above substituents of substituents            group (i) can in turn independently from each other be            substituted with one or more identical or different            substituents V;    -   n is independently 0, 1, 2, 3 or 4;    -   and the physiologically acceptable salts, derivatives, prodrugs,        solvates and stereoisomers thereof, including mixtures thereof        in all ratios.

In a preferred embodiment, a compound according to formula (I) and aboveembodiments is provided, wherein:

-   -   is independently substituted by a chemical group selected from        the group consisting of:

-   -   and the physiologically acceptable salts, derivatives, prodrugs,        solvates and stereoisomers thereof, including mixtures thereof        in all ratios.    -   In a preferred embodiment, a compound according to formula (I)        and above embodiments is provided, wherein:        -   W₁, W₂ together independently form “—N═N—, —C(O)—O—”; and            the physiologically acceptable salts, derivatives, prodrugs,            solvates and stereoisomers thereof, including mixtures            thereof in all ratios.    -   In a preferred embodiment, a compound according to formula (I)        and above embodiments is provided, wherein:        -   Y₁ is independently selected from the group consisting of            “—C(O)—, —N(R10)-C(O)—, —C(O)—N(R11)-, —OC(O)—, single            bond”;    -   and the physiologically acceptable salts, derivatives, prodrugs,        solvates and stereoisomers thereof, including mixtures thereof        in all ratios.    -   In a preferred embodiment, a compound according to formula (I)        and above embodiments is provided, wherein:        -   Z₁ is independently “O”;    -   and the physiologically acceptable salts, derivatives, prodrugs,        solvates and stereoisomers thereof, including mixtures thereof        in all ratios.    -   In a preferred embodiment, a compound according to formula (I)        and above embodiments is provided, wherein:        -   B is independently selected from the group consisting of            “4-chloro-phenyl, 3-trifluoromethyl-phenyl,            4-trifluoromethyl-phenyl, 4-trifluoromethylsulfanyl-phenyl,            4-trifluoromethoxy-phenyl,            3-chloro-4-trifluoromethoxy-phenyl,            3,5-bis-trifluoromethyl-phenyl, 4-isopropylphenyl,            4-tert.butyl-phenyl, 3,5-dichloro-phenyl,            4-chloro-2-fluoro-phenyl, 3-chloro-phenyl,            2-fluoro-5-trifluoromethyl-phenyl,            3-chloro-4-trifluoromethyl-phenyl, 3,4-dichloro-phenyl,            2,5-dichloro-phenyl, 2-methoxy-phenyl, 4-methoxy-phenyl,            4-nitro-phenyl, 4-bromo-phenyl, 5-chloro-2-methoxy-phenyl,            4-fluoro-phenyl, 3-bromo-4-fluoro-phenyl,            6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl”;    -   and the physiologically acceptable salts, derivatives, prodrugs,        solvates and stereoisomers thereof, including mixtures thereof        in all ratios.    -   In a preferred embodiment, a compound according to formula (I)        and above embodiments is provided, wherein:        -   R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14,            R15 are independently from each other selected from the            group consisting of: “hydrogen, alkyl, methyl, isopropyl,            tert.butyl, halogen, —F, —Br, —Cl, —CN, —CF₃, —SF₃, —OF₃,            —O-alkyl, —O-methyl, —NO₂, —S(O)₂-methyl”;    -   and the physiologically acceptable salts, derivatives, prodrugs,        solvates and stereoisomers thereof, including mixtures thereof        in all ratios.    -   In a preferred embodiment, a compound according to formula (I)        and above embodiments is provided, wherein:        -   V is independently selected from the group consisting of            “hydrogen, alkyl, methyl, isopropyl, tert.butyl, halogen,            —F, —Br, —Cl, —CN, —CF₃, —SF₃, —OH, —O-alkyl, —O-methyl,            —NO₂, —S(O)₂-methyl”;    -   and the physiologically acceptable salts, derivatives, prodrugs,        solvates and stereoisomers thereof, including mixtures thereof        in all ratios.    -   In a preferred embodiment, a compound according to formula (I)        and above embodiments is provided, wherein:        -   n is independently 0, 1 or 2;    -   and the physiologically acceptable salts, derivatives, prodrugs,        solvates and stereoisomers thereof, including mixtures thereof        in all ratios.

In a further preferred embodiment, a compound according to formulae (I)and above embodiments is provided, wherein:

-   -   W₁, W₂ together independently form “—N═N—, —C(O)—O—”;    -   Y₁ is independently selected from the group consisting of        “—C(O)—, —N(R10)-C(O)—, —C(O)—N(R11)-, —OC(O)—, single bond”;    -   Z₁ is independently “O”;    -   B is independently selected from the group consisting of        “4-chloro-phenyl, 3-trifluoromethyl-phenyl,        4-trifluoromethyl-phenyl, 4-trifluoromethylsulfanyl-phenyl,        4-trifluoromethoxy-phenyl, 3-chloro-4-trifluoromethoxy-phenyl,        3,5-bis-trifluoromethyl-phenyl, 4-isopropylphenyl,        4-tert.butyl-phenyl, 3,5-dichloro-phenyl,        4-chloro-2-fluoro-phenyl, 3-chloro-phenyl,        2-fluoro-5-trifluoromethyl-phenyl,        3-chloro-4-trifluoromethyl-phenyl, 3,4-dichloro-phenyl,        2,5-dichloro-phenyl, 2-methoxy-phenyl, 4-methoxy-phenyl,        4-nitro-phenyl, 4-bromo-phenyl, 5-chloro-2-methoxy-phenyl,        4-fluoro-phenyl, 3-bromo-4-fluoro-phenyl,        6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl”;    -   R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15        are independently from each other selected from the group        consisting of: “hydrogen, alkyl, methyl, isopropyl, tert.butyl,        halogen, —F, —Br, —Cl, —CN, —CF₃, —SF₃, —OF₃, —O-alkyl,        —O-methyl, —NO₂, —S(O)₂-methyl”    -   V is independently selected from the group consisting of        “hydrogen, alkyl, methyl, isopropyl, tert.butyl, halogen, —F,        —Br, —Cl, —CN, —CF₃, —SF₃, —OH, —O-alkyl, —O-methyl, —NO₂,        —S(O)₂-methyl”;    -   n is independently 0, 1 or 2;    -   and the physiologically acceptable salts, derivatives, prodrugs,        solvates and stereoisomers thereof, including mixtures thereof        in all ratios.

In another aspect, the object of the present invention has surprisinglybeen solved by providing a compound selected from the group consistingof:

Compound  1

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(4- chloro-phenyl)-ureido]-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidamide Compound  2

2-[3-(4-Chloro- phenyl)-ureido]-6-(2- oxo-2,3-dihydro- benzooxazole-6-carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidamide Compound  3

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(4- trifluoromethyl-phenyl)-ureido]- 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylicacid amide Compound  4

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(4- isopropyl-phenyl)-ureido]-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidamide Compound  5

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(4- chloro-phenyl)-propionylamino]- 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylicacid amide Compound  6

2-[3-(4-Chloro- phenyl)- propionylamino]-6-(2- oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide Compound  7

2-[3-(4-Isopropyl- phenyl)-ureido]-6-(2- oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide Compound  8

2-[3-(3,5-Dichloro- phenyl)-ureido]-6-(2- oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide Compound  9

6-(1H-Benzotriazole- 5-carbonyl)-2-[2-(4- chloro-2-fluoro-phenyl)-acetylamino]- 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine-3-carboxylic acid amide Compound 10

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6-(2- oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide Compound 11

6-(1H-Benzotriazole- 5-carbonyl)-2-[2-(3- chloro-phenyl)-acetylamino]-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylicacid amide Compound 12

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(3,5- dichloro-phenyl)-ureido]-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidamide Compound 13

2-[2-(3-Chloro- phenyl)-acetylamino]- 6-(2-oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide Compound 14

2-[2-(4-Chloro- phenyl)-acetylamino]- 6-(2-oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide Compound 15

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(4- chloro-2-fluoro-phenyl)-ureido]- 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylicacid amide Compound 16

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6- pyridin-3-ylmethyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylic acid amideCompound 17

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6- pyridin-2-ylmethyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylic acid amideCompound 18

2-[3-(4-Chloro- phenyl)-ureido]-6- pyridin-2-ylmethyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylic acid amideCompound 19

2-[3-(4-Chloro- phenyl)-ureide]-6- (pyridine-3-carbonyl)-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylic acid amideCompound 20

2-[3-(4-Chloro- phenyl)-ureido]-6- pyridin-4-ylmethyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylic acid amideCompound 21

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6- pyridin-4-ylmethyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylic acid amideCompound 22

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6-(2-pyridin-3-yl-acetyl)- 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine-3-carboxylic acid amide Compound 23

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6-(2-pyridin-4-yl-acetyl)- 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine-3-carboxylic acid amide Compound 24

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6-(3- pyridin-2-yl-propionyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidamide Compound 25

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(4- chloro-phenyl)-ureido]-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidmethyl ester Compound 26

2-[3-(4-Chloro- phenyl)-ureido]-6-(2- oxo-2,3-dihydro- benzooxazole-6-carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidmethyl ester Compound 27

1-[6-(1H- Benzotriazole-5- carbonyl)-3- (pyrrolidine-1-carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridin-2-yl]-3-(4-chloro-phenyl)-urea Compound 28

2-[3-(4-Chloro- phenyl)-ureido]-1H- indole-3,6- dicarboxylic acid 3-amide 6-[(2-oxo-2,3- dihydro-benzooxazol- 6-yl)-amide] Compound 29

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]- benzothiazole-6-carboxylic acid (2- oxo-2,3-dihydro- benzooxazol-6-yl)- amide Compound30

2-[3-(4- Trifluoromethyl- phenyl)-ureido]- benzothiazole-6- carboxylicacid (2- oxo-2,3-dihydro- benzooxazol-6-yl)- amide Compound 31

2-[3-(4-Chloro- phenyl)-ureido]- benzothiazole-6- carboxylic acid (2-oxo-2,3-dihydro- benzooxazol-6-yl)- amide Compound 32

2-[3-(4- Trifluoromethyl- phenyl)-ureido]- benzothiazole-6- carboxylicacid (1H- benzotriazol-5-yl)- amide Compound 33

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 3,5- dichloro-benzylamide Compound 34

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 4- chloro-benzylamide Compound 35

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(4- chloro-phenyl)- propyl]-amideCompound 36

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 2- fluoro-5- trifluoromethyl- benzylamideCompound 37

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2- (3,4-dichloro-phenyl)- ethyl]-amideCompound 38

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 2,5- dichloro-benzylamide Compound 39

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(4- chloro-phenyl)-ethyl]- amideCompound 40

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(4- chloro-phenyl)-1-hydroxymethyl-ethyl]- amide Compound 41

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 2- methoxy-benzylamide Compound 42

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(3- chloro-phenyl)-ethyl]- amideCompound 43

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(4- nitro-phenyl)-ethyl]- amideCompound 44

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(4- bromo-phenyl)-ethyl]- amideCompound 45

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 5- chloro-2-methoxy- benzylamide Compound46

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 4- chloro-2-fluoro- benzylamide Compound47

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(4- fluoro-phenyl)-ethyl]- amideCompound 48

[2-(1H-Benzotriazole- 5-carbonyl)-1,2,3,4- tetrahydro-isoquinolin-6-yl]-carbamic acid 3,5-dichloro-benzyl ester Compound 49

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 4- trifluoromethylsulfanyl- benzylamideCompound 50

3-(1H-Benzotriazol-5- ylcarbamoyl)-1,4,5,7- tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 4- trifluoromethyl-benzyl ester Compound51

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 3- bromo-4-fluoro- benzylamide Compound 52

3-(1H-Benzotriazol-5- ylcarbamoyl)-2,4,5,7- tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 3,5- dichloro-benzyl ester Compound 53

3-(1H-Benzotriazol-5- ylcarbamoyl)-2,4,5,7- tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 3,5- bis-trifluoromethyl- benzyl esterCompound 54

3-(1H-Benzotriazol-5- ylcarbamoyl)-2,4,5,7- tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 3- chloro-4- trifluoromethyl-benzyl esterCompound 55

3-(1H-Benzotriazol-5- ylcarbamoyl)-2,4,5,7- tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 3- trifluoromethyl-benzyl ester Compound56

3-(1H-Benzotriazol-5- ylcarbamoyl)-2,4,5,7- tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 4- trifluoromethylsulfanyl- benzyl esterCompound 57

3-(1H-Benzotriazol-5- ylcarbamoyl)-2,4,5,7- tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 4- trifluoromethoxy- benzyl ester Compound58

3-(1H-Benzotriazol-5- ylcarbamoyl)-2,4,5,7- tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 3- chloro-4- trifluoromethoxy- benzylester Compound 59

(1H-Benzotriazol-5- yl)-{3-[3-(4-methoxy- phenyl)-piperidine-1-carbonyl]-2,4,5,7- tetrahydro- pyrazolo[3,4- c]pyridin-6-yl}- methanoneCompound 60

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 4- trifluoromethoxy- benzylamide Compound61

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 4- trifluoromethyl- benzylamide Compound62

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid (6- methoxy-1,2,3,4- tetrahydro-naphthalen-2-yl)- amide Compound 63

3-{[6-(1H- Benzotriazole-5- carbonyl)-4,5,6,7- tetrahydro-2H-pyrazolo[3,4- c]pyridine-3- carbonyl]-amino}-3- (4-tert-butyl-phenyl)-propionic acid methyl ester

For the avoidance of doubt, if chemical name and chemical structure ofthe above illustrated compounds do not correspond by mistake, thechemical structure is regarded to unambigously define the compound.

All the above generically or explicitly disclosed compounds, includingpreferred subsets/embodiments of the herein disclosed formula (I) andCompounds 1 to 63, are hereinafter referred to as compounds of the(present) invention.

The nomenclature as used herein for defining compounds, especially thecompounds according to the invention, is in general based on the rulesof the IUPAC organisation for chemical compounds and especially organiccompounds.

The terms indicated for explanation of the above compounds of theinvention always, unless indicated otherwise in the description or inthe claims, have the following meanings:

The term “unsubstituted” means that the corresponding radical, group ormoiety has no substituents.

The term “substituted” means that the corresponding radical, group ormoiety has one or more substituents. Where a radical has a plurality ofsubstituents, and a selection of various substituents is specified, thesubstituents are selected independently of one another and do not needto be identical.

The terms “alkyl” or “A” as well as other groups having the prefix “alk”for the purposes of this invention refer to acyclic saturated orunsaturated hydrocarbon radicals which may be branched or straight-chainand preferably have 1 to 8 carbon atoms, i.e. C₁-C₈-alkanyls,C₂-C₈-alkenyls and C₂-C₈-alkynyls. Alkenyls have at least one C—C doublebond and alkynyls at least one C—C triple bond. Alkynyls mayadditionally also have at least one C—C double bond. Examples ofsuitable alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl,tert-pentyl, 2- or 3-methyl-pentyl, n-hexyl, 2-hexyl, isohexyl,n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl,n-hexadecyl, n-octadecyl, n-icosanyl, n-docosanyl, ethylenyl (vinyl),propenyl (—CH₂CH═CH₂; —CH═CH—CH₃, —C(═CH₂)—CH₃), butenyl, pentenyl,hexenyl, heptenyl, octenyl, octadienyl, octadecenyl, octadec-9-enyl,icosenyl, icos-11-enyl, (Z)-icos-11-enyl, docosnyl, docos-13-enyl,(Z)-docos-13-enyl, ethynyl, propynyl (—CH₂—C≡CH, —C≡C—CH₃), butynyl,pentynyl, hexynyl, heptynyl, octynyl. Especially preferred isC₁₋₄-alkyl. A C₁₋₄-alkyl radical is for example a methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl.

The term “(C₉-C₃₀)alkyl” for the purposes of this invention refers toacyclic saturated or unsaturated hydrocarbon radicals which may bebranched or straight-chain and have 9 to 30 carbon atoms, i.e.C₉-₃₀-alkanyls, C₉-₃₀-alkenyls and C₉-₃₀-alkynyls. C₉-₃₀-Alkenyls haveat least one C—C double bond and C₉-₃₀-alkynyls at least one C—C triplebond. C₉-₃₀-Alkynyls may additionally also have at least one C—C doublebond. Examples of suitable (C₉-C₃₀)alkyl radicals are tetradecyl,hexadecyl, octadecyl, eicosanyl, cis-13-docosenyl (erucyl),trans-13-docosenyl (brassidyl), cis-15-tetracosenyl (nervonyl) andtrans-15-tetracosenyl.

The term “cycloalkyl” for the purposes of this invention refers tosaturated and partially unsaturated non-aromatic cyclic hydrocarbongroups/radicals, having 1 to 3 rings, that contain 3 to 20, preferably 3to 12, most preferably 3 to 8 carbon atoms. The cycloalkyl radical mayalso be part of a bi- or polycyclic system, where, for example, thecycloalkyl radical is fused to an aryl, heteroaryl or heterocyclylradical as defined herein by any possible and desired ring member(s).The bonding to the compounds of the general formula can be effected viaany possible ring member of the cycloalkyl radical. Examples of suitablecycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl,cyclopentenyl and cyclooctadienyl. Especially preferred areC₃-C₉-cycloalkyl and C₄-C₈-cycloalkyl. A C₄-C₈-cycloalkyl radical is forexample a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

The term “heterocyclyl” for the purposes of this invention refers to amono- or polycyclic system of 3 to 20, preferably 5 or 6 to 14 ringatoms comprising carbon atoms and 1, 2, 3, 4, or 5 heteroatoms, inparticular nitrogen, oxygen and/or sulfur which are identical ordifferent. The cyclic system may be saturated, mono- or polyunsaturatedbut may not be aromatic. In the case of a cyclic system consisting of atleast two rings the rings may be fused or spiro- or otherwise connected.Such “heterocyclyl” radicals can be linked via any ring member. The term“heterocyclyl” also includes systems in which the heterocycle is part ofa bi- or polycyclic saturated, partially unsaturated and/or aromaticsystem, such as where the heterocycle is fused to an “aryl”,“cycloalkyl”, “heteroaryl” or “heterocyclyl” group as defined herein viaany desired and possible ring member of the heterocycyl radical. Thebonding to the compounds of the general formula can be effected via anypossible ring member of the heterocycyl radical. Examples of suitable“heterocyclyl” radicals are pyrrolidinyl, thiapyrrolidinyl, piperidinyl,piperazinyl, oxapiperazinyl, oxapiperidinyl, oxadiazolyl,tetrahydrofuryl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl,morpholinyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl,indolinylmethyl, imidazolidinyl, 2-aza-bicyclo[2.2.2]octanyl.

The term “aryl” for the purposes of this invention refers to a mono- orpolycyclic aromatic hydrocarbon systems having 3 to 14, preferably 5 to14, more preferably 6 to 10 carbon atoms. The term “aryl” also includessystems in which the aromatic cycle is part of a bi- or polycyclicsaturated, partially unsaturated and/or aromatic system, such as wherethe aromatic cycle is fused to an “aryl”, “cycloalkyl”, “heteroaryl” or“heterocyclyl” group as defined herein via any desired and possible ringmember of the aryl radical. The bonding to the compounds of the generalformula can be effected via any possible ring member of the arylradical. Examples of suitable “aryl” radicals are phenyl, biphenyl,naphthyl, 1-naphthyl, 2-naphthyl and anthracenyl, but likewise indanyl,indenyl, or 1,2,3,4-tetrahydronaphthyl. The most preferred aryl isphenyl.

The term “heteroaryl” for the purposes of this invention refers to a 3to 15, preferably 5 to 14, more preferably 5-, 6- or 7-membered mono- orpolycyclic aromatic hydrocarbon radical which comprises at least 1,where appropriate also 2, 3, 4 or 5 heteroatoms, preferably nitrogen,oxygen and/or sulfur, where the heteroatoms are identical or different.The number of nitrogen atoms is preferably 0, 1, 2, or 3, and that ofthe oxygen and sulfur atoms is independently 0 or 1. The term“heteroaryl” also includes systems in which the aromatic cycle is partof a bi- or polycyclic saturated, partially unsaturated and/or aromaticsystem, such as where the aromatic cycle is fused to an “aryl”,“cycloalkyl”, “heteroaryl” or “heterocyclyl” group as defined herein viaany desired and possible ring member of the heteroaryl radical. Thebonding to the compounds of the general formula can be effected via anypossible ring member of the heteroaryl radical. Examples of suitable“heteroaryl” are acridinyl, benzdioxinyl, benzimidazolyl,benzisoxazolyl, benzodioxolyl, benzofuranyl, benzothiadiazolyl,benzothiazolyl, benzothienyl, benzoxazolyl, carbazolyl, cinnolinyl,dibenzofuranyl, dihydrobenzothienyl, furanyl, furazanyl, furyl,imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl,isobenzylfuranyl, isoindolyl, isoquinolinyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, quinolyl, quinoxalinyl,tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiophenyl, triazinyl,triazolyl.

For the purposes of the present invention, the terms “alkyl-cycloalkyl”,“cycloalkylalkyl”, “alkyl-heterocyclyl”, “heterocyclylalkyl”,“alkyl-aryl”, “arylalkyl”, “alkyl-heteroaryl” and “heteroarylalkyl” meanthat alkyl, cycloalkyl, heterocycl, aryl and heteroaryl are each asdefined above, and the cycloalkyl, heterocyclyl, aryl and heteroarylradical is bonded to the compounds of the general formula via an alkylradical, preferably C₁-C₈-alkyl radical, more preferably C₁-C₄-alkylradical.

The term “alkyloxy” or “alkoxy” for the purposes of this inventionrefers to an alkyl radical according to above definition that isattached to an oxygen atom. The attachment to the compounds of thegeneral formula is via the oxygen atom. Examples are methoxy, ethoxy andn-propyloxy, propoxy, isopropoxy. Preferred is “C₁-C₄-alkyloxy” havingthe indicated number of carbon atoms.

The term “cycloalkyloxy” or “cycloalkoxy” for the purposes of thisinvention refers to a cycloalkyl radical according to above definitionthat is attached to an oxygen atom. The attachment to the compounds ofthe general formula is via the oxygen atom. Examples are cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy,cyclooctyloxy. Preferred is “C₃-C₉cycloalkyloxy” having the indicatednumber of carbon atoms.

The term “heterocyclyloxy” for the purposes of this invention refers toa heterocyclyl radical according to above definition that is attached toan oxygen atom. The attachment to the compounds of the general formulaeis via the oxygen atom. Examples are pyrrolidinyloxy,thiapyrrolidinyloxy, piperidinyloxy, piperazinyloxy.

The term “aryloxy” for the purposes of this invention refers to an arylradical according to above definition that is attached to an oxygenatom. The attachment to the compounds of the general formula is via theoxygen atom. Examples are phenyloxy, 2-naphthyloxy, 1-naphthyloxy,biphenyloxy, indanyloxy. Preferred is phenyloxy.

The term “heteroaryloxy” for the purposes of this invention refers to aheteroaryl radical according to above definition that is attached to anoxygen atom. The attachment to the compounds of the general formula isvia the oxygen atom. Examples are pyrrolyloxy, thienyloxy, furyloxy,imidazolyloxy, thiazolyloxy.

The term “carbonyl” or “carbonyl moiety” for the purposes of thisinvention refers to a —C(O)— group.

The term “alkylcarbonyl” for the purposes of this invention refers to a“alkyl-C(O)—” group, wherein alkyl is as defined herein.

The term “alkoxycarbonyl” or “alkyloxycarbonyl” for the purposes of thisinvention refers to a “alkyl-O—C(O)—” group, wherein alkyl is as definedherein.

The term “alkoxyalkyl” for the purposes of this invention refers to a“alkyl-O-alkyl-” group, wherein alkyl is as defined herein.

The term “haloalkyl” for the purposes of this invention refers to analkyl group as defined herein comprising at least one carbon atomsubstituent with at least one halogen as defined herein.

The term “halogen”, “halogen atom”, “halogen substituent” or “Hal” forthe purposes of this invention refers to one or, where appropriate, aplurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl,chloro), or iodine (I, iodo) atoms. The designations “dihalogen”,“trihalogen” and “perhalogen” refer respectively to two, three and foursubstituents, where each substituent can be selected independently fromthe group consisting of fluorine, chlorine, bromine and iodine.“Halogen” preferably means a fluorine, chlorine or bromine atom.Fluorine is most preferred, when the halogens are substituted on analkyl (haloalkyl) or alkoxy group (e.g. CF₃ and CF₃O).

The term “hydroxyl” or “hydroxy” means an OH group.

The term “composition”, as in pharmaceutical composition, for thepurposes of this invention is intended to encompass a product comprisingthe active ingredient(s), and the inert ingredient(s) that make up thecarrier, as well as any product which results, directly or indirectly,from combination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound of thepresent invention and a pharmaceutically acceptable carrier.

The terms “administration of” and “administering a” compound should beunderstood to mean providing a compound of the invention or a prodrug ofa compound of the invention to the individualist need.

As used herein, the term “effective amount” refers to any amount of adrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

All stereoisomers of the compounds of the invention are contemplated,either in a mixture or in pure or substantially pure form. The compoundsof the invention can have asymmetric centers at any of the carbon atoms.Consequently, they can exist in the form of their racemates, in the formof the pure enantiomers and/or diastereomers or in the form of mixturesof these enantiomers and/or diastereomers. The mixtures may have anydesired mixing ratio of the stereoisomers.

Thus, for example, the compounds of the invention which have one or morecenters of chirality and which occur as racemates or as diastereomermixtures can be fractionated by methods known per se into their opticalpure isomers, i.e. enantiomers or diastereomers. The separation of thecompounds of the invention can take place by column separation on chiralor nonchiral phases or by recrystallization from an optionally opticallyactive solvent or with use of an optically active acid or base or byderivatization with an optically active reagent such as, for example, anoptically active alcohol, and subsequent elimination of the radical.

The compounds of the invention may be present in the form of theirdouble bond isomers as “pure” E or Z isomers, or in the form of mixturesof these double bond isomers.

Where possible, the compounds of the invention may be in the form of thetautomers, such as keto-enol tautomers.

It is likewise possible for the compounds of the invention to be in theform of any desired prodrugs such as, for example, esters, carbonates,carbamates, ureas, amides or phosphates, in which cases the actuallybiologically active form is released only through metabolism. Anycompound that can be converted in vivo to provide the bioactive agent(i.e. compounds of the invention) is a prodrug within the scope andspirit of the invention.

Various forms of prodrugs are well known in the art and are describedfor instance in:

(i) Wermuth C G et al., Chapter 31: 671-696, The Practice of MedicinalChemistry, Academic Press 1996;

(ii) Bundgaard H, Design of Prodrugs, Elsevier 1985; and

(iii) Bundgaard H, Chapter 5: 131-191, A Textbook of Drug Design andDevelopment, Harwood Academic Publishers 1991.

Said references are incorporated herein by reference.

It is further known that chemical substances are converted in the bodyinto metabolites which may where appropriate likewise elicit the desiredbiological effect—in some circumstances even in more pronounced form.

Any biologically active compound that was converted in vivo bymetabolism from any of the compounds of the invention is a metabolitewithin the scope and spirit of the invention.

The compounds of the invention can, if they have a sufficiently basicgroup such as, for example, a secondary or tertiary amine, be convertedwith inorganic and organic acids into salts. The pharmaceuticallyacceptable salts of the compounds of the invention are preferably formedwith hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid,phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonicacid, formic acid, acetic acid, sulfoacetic acid, trifluoroacetic acid,oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid,racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid,lactic acid, citric acid, taurocholic acid, glutaric acid, stearic acid,glutamic acid or aspartic acid. The salts which are formed are, interalia, hydrochlorides, chlorided, hydrobromides, bromides, iodides,sulfates, phosphates, methanesulfonates, tosylates, carbonates,bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates,malonates, maleates, succinates, tartrates, malates, embonates,mandelates, fumarates, lactates, citrates, glutarates, stearates,aspartates and glutamates. The stoichiometry of the salts formed fromthe compounds of the invention may moreover be an integral ornon-integral multiple of one.

The compounds of the invention can, if they contain a sufficientlyacidic group such as, for example, the carboxy, sulfonic acid,phosphoric acid or a phenolic group, be converted with inorganic andorganic bases into their physiologically tolerated salts. Examples ofsuitable inorganic bases are ammonium, sodium hydroxide, potassiumhydroxide, calcium hydroxide, and of organic bases are ethanolamine,diethanolamine, triethanolamine, ethylenediamine, t-butylamine,t-octylamine, dehydroabietylamine, cyclohexylamine,dibenzylethylene-diamine and lysine. The stoichiometry of the saltsformed from the compounds of the invention can moreover be an integralor non-integral multiple of one.

It is likewise possible for the compounds of the invention to be in theform of their solvates and, in particular, hydrates which can beobtained for example by crystallization from a solvent or from aqueoussolution. It is moreover possible for one, two, three or any number ofsolvate or water molecules to combine with the compounds of theinvention to give solvates and hydrates.

By the term “solvate” is meant a hydrate, an alcoholate, or othersolvate of crystallization.

It is known that chemical substances form solids which exist indifferent order states which are referred to as polymorphic forms ormodifications. The various modifications of a polymorphic substance maydiffer greatly in their physical properties. The compounds of theinvention can exist in various polymorphic forms and certainmodifications may moreover be metastable. All these polymorphic forms ofthe compounds are to be regarded as belonging to the invention.

The compounds of the invention are surprisingly characterized by astrong and/or selective inhibition of autotaxin.

Due to their surprisingly strong and/or selective enzyme inhibition, thecompounds of the invention can be advantageously administered at lowerdoses compared to other less potent or selective inhibitors of the priorart while still achieving equivalent or even superior desired biologicaleffects. In addition, such a dose reduction may advantageously lead toless or even no medicinal adverse effects. Further, the high inhibitionselectivity of the compounds of the invention may translate into adecrease of undesired side effects on its own regardless of the doseapplied.

The compounds of the invention being autotaxin inhibitors generally havean inhibition constant IC₅₀ of less than about 30 μM, and preferablyless than about 5 μM.

The object of the present invention has surprisingly been solved inanother aspect by providing the use of a compound of the invention asautotaxin inhibitor.

The terms “inhibiting, inhibition and/or retardation” are intended torefer for the purposes of the present invention to as follows: “partialor complete inhibiting, inhibition and/or retardation”. In this case, itis within the specialist knowledge of the average person skilled in theart to measure and determine such inhibiting, inhibition, and/orretardation by means of the usual methods of measurement anddetermination. Thus, a partial inhibiting, inhibition and/orretardation, for example, can be measured and determined in relation toa complete inhibiting, inhibition and/or retardation.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for the preparation of a compoundof the invention, comprising the steps:

-   -   (a) reacting a compound of the formula (II),

-   -   -   wherein W₁, W₂, R1, R2 have the meanings as indicated            hereinwith, with a compound of the formula (III)

-   -   -   wherein L is selected from the group consisting of:

-   -   -   and wherein Z₁, Y₂, R3, R4, B, n have the meanings as            indicated hereinwith, to yield a compound according to            formula (I) as indicated hereinwith, in which Y₁ denotes            “—C(O)—”;

    -   or

    -   (b) reacting a compound of the formula (II)

-   -   -   wherein W₁, W₂, R1, R2 have the meanings as indicated            hereinwith, with a compound L selected from the group            consisting of:

-   -   -   to yield a compound of the formula (IIa)

-   -   -   wherein W₁, W₂, R1, R2 have the meanings as indicated            hereinwith; further reacting the compound of formula (IIa)            with a compound of formula (IV)

-   -   -   wherein R3, R4, B, n have the meanings as indicated            hereinwith, to yield a compound according to formula (I) as            indicated hereinwith, in which Z₁ denotes “O” and Y₂ denotes            “—N(R16)-” and R16 denotes “H”;

    -   or

    -   (c) reacting a compound of the formula (Va) or (Vb)

-   -   -   wherein m and n independently are 0, 1 or 2, with a compound            of the formula (III)

-   -   -   wherein L is selected from the group consisting of:

-   -   -   and wherein Z₁, Y₂, R3, R4, B, n have the meanings as            indicated in claim 1, to yield a compound according to            formula (I) as indicated in claims 1 and 2, in which Y₁            denotes “—C(R12)(R13)- and R12, R13 both denote “H” or Y₁            denotes “—C(O)—”,

    -   or

    -   (d) reacting a compound of the formula (VI)

HO(O)C-L  (VI)

-   -   -   wherein L is selected from the group consisting of:

-   -   -   with a compound of the formula (VII)

-   -   -   wherein W₁, W₂, R1, R2 have the meanings as indicated            hereinwith; to yield a compound of the formula (VIII)

-   -   -   wherein W₁, W₂, R1, R2 have the meanings as indicated            hereinwith; further reacting the compound of formula (VIII)            with a compound of formula (IV)

-   -   -   wherein R3, R4, B, n have the meanings as indicated            hereinwith, to yield a compound according to formula (I) as            indicated hereinwith, in which Y₁ denotes “—N(R10)-C(O)—”,            R10 denotes “H”, Z₁ denotes “O”, Y₂ denotes “—N(R16)-” and            R16 denotes “H”;

    -   or

    -   (e) reacting a compound of the formula (IX)

-   -   -   wherein L is selected from the group consisting of:

-   -   -   and wherein Z₁, Y₂, R3, R4, B, n have the meanings as            indicated hereinwith, with a compound of the formula (VII)

-   -   -   wherein W₁, W₂, R1, R2 have the meanings as indicated            hereinwith; to yield a compound according to formula (I) as            indicated hereinwith, in which Y₁ denotes “—N(R10)-C(O)—”            and R10 denotes “H”.

    -   or

    -   (f) reacting a compound of the formula (X)

-   -   -   wherein W₁, W₂, R1, R2, Y₁ have the meanings as indicated            hereinwith, wherein L is selected from the group consisting            of:

-   -   -   with a compound of formula (XI)

-   -   -   wherein R3, R4, B, n have the meanings as indicated            hereinwith, to yield a compound according to formula (I) as            indicated hereinwith, in which Z₁ denotes “O”, Y₂ denotes            “—N(R16)-” and R16 denotes “H”.

All crude products were subjected to standard chromatography usingsolvent mixtures containing methanol, ethanol, isopropanol, n-hexane,cyclohexane or petrol ether, respectively.

For a further detailed description of the manufacturing processes,please refer also to the examples and the following general descriptionof the preferred conditions.

A physiologically acceptable salt of a compound of the invention canalso be obtained by isolating and/or treating the compound of theinvention obtained by the described reaction with an acid or a base.

The compounds of the invention and also the starting materials for theirpreparation are, are prepared by methods as described in the examples orby methods known per se, as described in the literature (for example instandard works, such as Houben-Weyl, Methoden der Organischen Chemie[Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; OrganicReactions, John Wiley & Sons, Inc., New York), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

The starting materials for the claimed process may, if desired, also beformed in situ by not isolating them from the reaction mixture, butinstead immediately converting them further into the compounds of theinvention. On the other hand, it is possible to carry out the reactionstepwise.

Preferably, the reaction of the compounds is carried out in the presenceof a suitable solvent, which is preferably inert under the respectivereaction conditions. Examples of suitable solvents are hydrocarbons,such as hexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichlorethylene, 1,2-dichloroethane,tetrachloromethane, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone(NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethylsulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene;esters, such as ethyl acetate, or mixtures of the said solvents ormixtures with water. Polar solvents are in general preferred. Examplesfor suitable polar solvents are chlorinated hydrocarbons, alcohols,glycol ethers, nitriles, amides and sulfoxides or mixtures thereof. Morepreferred are amides, especially dimethylformamide (DMF).

As stated above, the reaction temperature is between about −100° C. and300° C., depending on the reaction step and the conditions used.

Reaction times are generally in the range between some minutes andseveral days, depending on the reactivity of the respective compoundsand the respective reaction conditions. Suitable reaction times arereadily determinable by methods known in the art, for example reactionmonitoring. Based on the reaction temperatures given above, suitablereaction times generally lie in the range between 10 min and 48 hrs.

A base of a compound of the invention can be converted into theassociated acid-addition salt using an acid, for example by reaction ofequivalent amounts of the base and the acid in a preferably inertsolvent, such as ethanol, followed by evaporation. Suitable acids forthis reaction are, in particular, those which give physiologicallyacceptable salts. Thus, it is possible to use inorganic acids, forexample sulfuric acid, sulfurous acid, dithionic acid, nitric acid,hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as, for example, orthophosphoric acid, sulfamicacid, furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, hexanoic acid, octanoic acid, decanoic acid,hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid,malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid,lactic acid, tartaric acid, malic acid, citric acid, gluconic acid,ascorbic acid, nicotinic acid, isonicotinic acid, methane- orethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylicacid, p-toluenesulfonic acid, glycolic acid, embonic acid,chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline,glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid,cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalenemono- and-disulfonic acids or laurylsulfuric acid.

Salts with physiologically unacceptable acids, for example picrates, canbe used to isolate and/or purify the compounds of the invention.

On the other hand, compounds of the invention can be converted into thecorresponding metal salts, in particular alkali metal salts or alkalineearth metal salts, or into the corresponding ammonium salts, using bases(for example sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate). Suitable salts are furthermore substitutedammonium salts, for example the dimethyl-, diethyl- anddiisopropylammonium salts, monoethanol-, diethanol- anddiisopropanolammonium salts, cyclohexyl- and dicyclohexylammonium salts,dibenzylethylenediammonium salts, furthermore, for example, salts witharginine or lysine.

If desired, the free bases of the compounds of the invention can beliberated from their salts by treatment with strong bases, such assodium hydroxide, potassium hydroxide, sodium carbonate or potassiumcarbonate, so long as no further acidic groups are present in themolecule. In the cases where the compounds of the invention have freeacid groups, salt formation can likewise be achieved by treatment withbases. Suitable bases are alkali metal hydroxides, alkaline earth metalhydroxides or organic bases in the form of primary, secondary ortertiary amines.

Every reaction step described herein can optionally be followed by oneor more working up procedures and/or isolating procedures. Suitable suchprocedures are known in the art, for example from standard works, suchas Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart). Examples for suchprocedures include, but are not limited to evaporating a solvent,distilling, crystallization, fractionised crystallization, extractionprocedures, washing procedures, digesting procedures, filtrationprocedures, chromatography, chromatography by HPLC and dryingprocedures, especially drying procedures in vacuo and/or elevatedtemperature.

The object of the present invention has surprisingly been solved inanother aspect by providing a medicament comprising at least onecompound of the invention.

The object of the present invention has surprisingly been solved inanother aspect by providing a medicament comprising at least onecompound of the invention for use in the treatment and/or prophylaxis ofphysiological and/or pathophysiological conditions, which are caused,mediated and/or propagated by increased lysophosphatic acid levelsand/or the activation of autotaxin. A corresponding use for thepreparation of a medicament for the treatment and/or prophylaxis of theaforementioned conditions is intended to be comprised.

The object of the present invention has surprisingly been solved inanother aspect by providing a medicament comprising at least onecompound of the invention for use in the treatment and/or prophylaxis ofphysiological and/or pathophysiological conditions selected from thegroup consisting of: “cancer, tumour, malignant tumours, benign tumours,solid tumours, sarcomas, carcinomas, hyperproliferative disorders,carcinoids, Ewing sarcomas, Kaposi sarcomas, brain tumours, tumoursoriginating from the brain and/or the nervous system and/or themeninges, gliomas, glioblastomas, neuroblastomas, stomach cancer, kidneycancer, kidney cell carcinomas, prostate cancer, prostate carcinomas,connective tissue tumours, soft tissue sarcomas, pancreas tumours, livertumours, head tumours, neck tumours, laryngeal cancer, oesophagealcancer, thyroid cancer, osteosarcomas, retinoblastomas, thymoma,testicular cancer, lung cancer, lung adenocarcinoma, small cell lungcarcinoma, bronchial carcinomas, breast cancer, mamma carcinomas,intestinal cancer, colorectal tumours, colon carcinomas, rectumcarcinomas, gynaecological tumours, ovary tumours/ovarian tumours,uterine cancer, cervical cancer, cervix carcinomas, cancer of body ofuterus, corpus carcinomas, endometrial carcinomas, urinary bladdercancer, urogenital tract cancer, bladder cancer, skin cancer, epithelialtumours, squamous epithelial carcinoma, basaliomas, spinaliomas,melanomas, intraocular melanomas, leukaemias, monocyte leukaemia,chronic leukaemias, chronic myelotic leukaemia, chronic lymphaticleukemia, acute leukaemias, acute myelotic leukaemia, acute lymphaticleukemia, lymphomas, angiogenesis, arteriosclerosis, opthalmic diseases,choroidal neovascularization, diabetic retinopathy, inflammatorydiseases, arthritis, neurodegeneration, restenosis, wound healing and/ortransplant rejection”. A corresponding use for the preparation of amedicament for the treatment and/or prophylaxis of the aforementionedconditions is intended to be comprised.

Compounds of the invention may be used in combination with one or moreother active substances (ingredients, drugs) in the treatment,prevention, suppression or amelioration of diseases or conditions forwhich compounds of the invention or the other substances have utility.Typically the combination of the drugs is safer or more effective thaneither drug alone, or the combination is safer or more effective thanwould it be expected based on the additive properties of the individualdrugs. Such other drug(s) may be administered, by a route and in anamount commonly used contemporaneously or sequentially with a compoundof the invention. When a compound of the invention is usedcontemporaneously with one or more other drugs, a combination productcontaining such other drug(s) and the compound of the invention ispreferred. However, combination therapy also includes therapies in whichthe compound of the invention and one or more other drugs areadministered on different overlapping schedules. It is contemplated thatwhen used in combination with other active ingredients, the compound ofthe present invention or the other active ingredient or both may be usedeffectively in lower doses than when each is used alone. Accordingly,the pharmaceutical compositions of the present invention include thosethat contain one or more other active ingredients, in addition to acompound of the invention.

Examples of other active substances (ingredients, drugs) that may beadministered in combination with a compound of the invention, and eitheradministered separately or in the same pharmaceutical composition,include, but are not limited to the compounds classes and specificcompounds listed in Table 1:

TABLE 1 Alkylating agents Cyclophosphamide Lomustine BusulfaneProcarbazine Ifosfamide Altretamine Melphalane EstramustinphosphateHexamethylmelamine Mechlorethamine Thiotepa Streptozocine ChlorambucilTemozolomide Dacarbazine Semustine Carmustine Platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(AeternaZentaris) Carboxyphthalatoplatinum Satraplatin (JohnsonTetraplatin Matthey) Ormiplatin BBR-3464 (Hoffrnann-La Iproplatin Roche)SM-11355 (Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycine 5-FluoruracilFludarabine Floxuridine Pentostatine 2-Chlordesoxyadenosine Raltitrexede6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-Fluordesoxycytidine Irofulven(MGI Pharma) Methotrexate DMDC (Hoffmann-La Roche) IdatrexateEthinylcytidine (Taiho) Topoisomerase Amsacrine Rubitecane (SuperGen)inhibitors Epirubicine Exatecanmesylate (Daiichi) Etoposide Quinamed(ChemGenex) Teniposide or Mitoxantrone Gimatecane (Sigma- Tau)Irinotecane (CPT-11) Diflomotecane (Beaufour- 7-Ethyl-10- Ipsen)hydroxycamptothecine TAS-103 (Taiho) Topotecane Elsamitrucine (Spectrum)Dexrazoxanet (TopoTarget) J-107088 (Merck & Co) Pixantrone(Novuspharrna) BNP-1350 (BioNumerik) Rebeccamycin-Analogue CKD-602(Chong Kun Dang) (Exelixis) KW-2170 (Kyowa Hakko) BBR-3576(Novuspharrna) Antitumour antibiotics Dactinomycin (ActinomycinAmonafide D) Azonafide Doxorubicin (Adriamycin) AnthrapyrazoleDeoxyrubicin Oxantrazole Valrubicin Losoxantrone Daunorubicin(Daunomycin) Bleomycinsulfate (Blenoxan) Epirubicin BleomycinacidTherarubicin Bleomycin A Idarubicin Bleomycin B Rubidazone Mitomycin CPlicamycinp MEN-10755 (Menarini) Porfiromycin GPX-100 (GemCyanomorpholinodoxorubicin Pharmaceuticals) Mitoxantron (Novantron)Antimitotic agents Paclitaxel SB 408075 Docetaxel (GlaxoSmithKline)Colchicin E7010 (Abbott) Vinblastine PG-TXL (Cell Therapeutics)Vincristine IDN 5109 (Bayer) Vinorelbine A 105972 (Abbott) Vindesine A204197 (Abbott) Dolastatine 10 (NCI) LU 223651 (BASF) Rhizoxine(Fujisawa) D 24851 (ASTA Medica) Mivobuline (Warner-Lambert) ER-86526(Eisai) Cemadotine (BASF) Combretastatine A4 (BMS) RPR 109881A (Aventis)Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilon B(Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel(Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly)!DN-5109 (Indena) Vinflunine (Fabre) AVLB (Prescient Auristatine PE(Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) BMS 247550 (BMS)BNP- 7787 (BioNumerik) BMS 184476 (BMS) CA-4-Prodrug (OXiGENE) BMS188797 (BMS) Dolastatin-10 (NrH) Taxoprexine (Protarga) CA-4 (OXiGENE)Aromatase inhibitors Aminoglutethimide Exemestane Letrozole Atamestane(BioMedicines) Anastrazole YM-511 (Yamanouchi) FormestaneThymidylatesynthase Pemetrexed (Eli Lilly) Nolatrexed (Eximias)inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys) DNA antagonistsTrabectedine (PharmaMar) Mafosfamide (Baxter Glufosfamide (BaxterInternational) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-Benzylguanine (Paligent)Thymectacine (NewBiotics) Edotreotide (Novartis) FarnesyltransferaseArglabine (NuOncology Labs) Tipifarnibe (Johnson & inhibitorsIonafarnibe (Schering- Johnson) Plough) Perillylalcohol (DOR BAY-43-9006(Bayer) BioPharma) Pump inhibitors CBT-1 (CBA Pharma)Zosuquidar-Trihydrochloride Tariquidar (Xenova) (Eli Lilly) MS-209(Schering AG) Biricodar-Dicitrate (Vertex) HistoneacetyltransferaseTacedinaline (Pfizer) Pivaloyloxymethylbutyrate inhibitors SAHA (AtonPharma) (Titan) MS-275 (Schering AG) Depsipeptide (Fujisawa)Metalloproteinase Neovastat (Aeterna CMT -3 (CollaGenex) inhibitors/Laboratories) BMS-275291 (Celltech) Ribonucleosidereduktase Marimastat(British Biotech) Tezacitabine (Aventis) inhibitors Galliummaltolate(Titan) Didox (Molecules for Health) Triapine (Vion) TNF-alpha agonists/Virulizine (Lorus Revimide (Celgene) antagonists Therapeutics) CDC-394(Celgene) Endothelin-A Atrasentane (Abbot) YM-598 (Yamanouchi) receptorantagonists ZD-4054 (AstraZeneca) Retinoic acid Fenretinide (Johnson &Alitretinoin (Ligand) receptor agonists Johnson) LGD-1550 (Ligand)Immunomodulators Interferon Dexosome therapy (Anosys) Oncophage(Antigenics) Pentrix (Australian Cancer GMK (Progenies) Technology)Adenocarzinoma vaccine JSF-154 (Tragen) (Biomira) Cancer vaccine(Intercell) CTP-37 (AVI BioPharma) Noreline (Biostar) JRX-2 (Immuno-Rx)BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) Synchrovaxvaccine (CTL 13-Alethine (Dovetail) Immuno) CLL-Thera (Vasogen) Melanomavaccine (CTL Immuno) p21-RAS vaccine (GemVax) Hormonal and anti-Estrogens Prednisone hormonal agents Conjugated EstrogensMethylprednisolone Ethinylestradiole Prednisolone ChlorotrianisenAminoglutethimide Idenestrole Leuprolide HydroxyprogesteroncaproateGoserelin Medroxyprogesterone Leuporelin Testosterone CetrorelixTestosteronpropionate Bicalutamide Fluoxymesterone FlutamideMethyltestosterone Octreotide Diethylstilbestrole Nilutamide MegestroleMitotane Tamoxifen P-04 (Novogen) Toremofine 2-MethoxyoestradiolDexamethasone (EntreMed) Arzoxifen (Eli Lilly) Photodynamic agentsTalaporfine (Light Sciences) Pd-Bacteriopheophorbide Theralux(Theratechnologies) (Yeda) Motexafin Gadolinium Lutetium-Texaphyrine(Pharmacyclics) (Pharmacyclics) Hypericine Tyrosinkinase Imatinib(Novartis) Kahalid F (PharmaMar) inhibitors Leflunomid CEP- 701(Cephalon) (Sugen/Pharmacia) CEP-751 (Cephalon) ZDI839 (AstraZeneca)MLN518 (Millenium) Erlotinib (Oncogene Science) PKC412 (Novartis)Canertjnib (Pfizer) Phenoxodiol O Squalamin (Genaera) Trastuzumab(Genentech) SU5416 (Pharmacia) C225 (ImClone) SU6668 (Pharmacia) rhu-Mab(Genentech) ZD4190 (AstraZeneca) MDX-H210 (Medarex) ZD6474 (AstraZeneca)2C4 (Genentech) Vatalanib (Novartis) MDX-447 (Medarex) PKI166 (Novartis)ABX-EGF (Abgenix) GW2016 (GlaxoSmithKline) IMC-1C11 (ImClone) EKB-509(Wyeth) EKB-569 (Wyeth) Different agents SR-27897 (CCK-A inhibitor,BCX-1777 (PNP inhibitor, Sanofi-Synthelabo) BioCryst) Tocladesine(cyclic-AMP Ranpirnase (Ribonuclease agonist, Ribapharm) stimulans,Alfacell) Alvocidib (CDK inhibitor, Galarubicin (RNA synthesis Aventis)inhibitor, Dong-A) CV-247 (COX-2 Inhibitor, Ivy Tirapazamin (reducingagent, Medical) SRI International) P54 (COX-2 inhibitor, N-Acetylcystein(reducing Phytopharm) agent, Zambon) CapCell ™ (CYP450 R-Flurbiprofen(NF-kappaB stimulans, Bavarian Nordic) inhibitor, Encore) GCS-IOO (gal3antagonist, 3CPA (NF-kappaB inhibitor, GlycoGenesys) Active Biotech)G17DT immunogen (Gastrin Seocalcitol (Vitamin-D inhibitor, Aphton)receptor agonist, Leo) Efaproxiral (Oxygenator, 131-I-TM-601 (DNA AllosTherapeutics) antagonist, TransMolecular) PI-88 (Heparanase inhibitor,Eflornithin (ODC inhibitor, Progen) ILEX Oncology) Tesmilifen (HistamineMinodronic acid (Osteoclasts antagonist, YM BioSciences) inhibitor,Yamanouchi) Histamine (Histamine-H2 Indisulam (p53 stimulans, receptoragonist, Maxim) Eisai) Tiazofurin (IMPDH inhibitor, Aplidin (PPTinhibitor, Ribapharm) PharmaMar) Cilengitide (Integrine Rituximab (CD20antibody, antagonist, Merck KGaA) Genentech) SR-31747 (IL-1 antagonist,Gemtuzumab (CD33 Sanofi-Synthelabo) antibody, Wyeth Ayerst) CCI-779(mTOR kinase PG2 (Hematopoesis inhibitor, Wyeth) enhancer,Pharmagenesis) Exisulind (PDE-V inhibitor, Immunol ™ (Triclosan oralCell Pathways) irrigation, Endo) CP-461 (PDE-V inhibitor, CellTriacetyluridine (Uridine Pathways) prodrug, Wellstat) AG-2037 (GARTinhibitor, SN-4071 (sarcoma agent, Pfizer) Signature BioScience) WX-UK1(Plasminogen TransMID-107 ™ activator inhibitor, Wilex) (Immunotoxine,KS PBI-1402 (PMN stimulans, Biomedix) ProMetic LifeSciences) PCK-3145(Apoptosis Bortezomib (Proteasome enhancer, Procyon) inhibitor,Millennium) Doranidazole (Apoptosis SRL-172 (T-cell stimulans, enhancer,Pola) SR Pharma) CHS-828 (cytotoxic agent, TLK-286 (Glutathione-S- Leo)transferase inhibitor, Telik) trans-Retinoic acid PT-100 (Growth factor(Differentiator, NIH) agonist, Point Therapeutics) MX6 (Apoptosisenhancer, Midostaurin (PKC inhibitor, MAXIA) Novartis) Apomin (Apoptosisenhancer, Bryostatin-1 (PKC stimulans, ILEX Oncology) GPC Biotech)Urocidine (Apoptosis CDA-II (Apoptosis enhancer, enhancer, Bioniche)Everlife) Ro-31-7453 (Apoptosis SDX-101 (Apoptosis enhancer, La Roche)enhancer, Salmedix) Brostallicin (Apoptosis Ceflatonin (Apoptosisenhancer, Pharmacia) enhancer, ChemGenex)

In a preferred embodiment, a compound of the invention is administeredin combination with one or more known anti-tumor agents, such as thefollowing: estrogen receptor modulators, androgen receptor modulators,retinoid receptor modulators, cytotoxics, antiproliferative agents,prenyl proteintransferase inhibitors, HMG-CoA-reductase inhibitors, HIVprotease inhibitors, reverse transcriptase inhibitors, angiogenesisinhibitors.

The compounds of the invention are in particular well suited foradministration in combination with radiotherapy. The synergistic effectsof VEGF inhibition in combination with radiotherapy are known to theskilled artisan (WO 00/61186).

The term “estrogen receptor modulators” in the course of the presentinvention refers to compounds that interfere with or inhibit the bindingof estrogen to estrogen receptor—independently from the mode of action.Non-limiting examples of estrogen receptor modulators are tamoxifen,raloxifen, idoxifen, LY353381, LY 117081, toremifen, fulvestrant,4-[7-(2,2-Dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl-2,2-dimethyl-propanoate,4,4′-Dihydroxybenzophenon-2,4-dinitrophenylhydrazone and SH646.

The term “androgen receptor modulators” in the course of the presentinvention refers to compounds that interfere with or inhibit the bindingof androgens to androgen receptor—independently from the mode of action.Non-limiting examples of androgen receptor modulators are finasterideand other 5alpha-reductase inhibitors, nilutamide, flutamide,bicalutamide, liarozole and abirateron acetate.

The term “retinoid receptor modulators” in the course of the presentinvention refers to compounds that interfere with or inhibit the bindingof retinoids to retinoid receptor—independently from the mode of action.Non-limiting examples of retinoid receptor modulators are bexaroten,tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,alpha-difluoromethylornithine, ILX23-7553,trans-N-(4′-Hydroxyphenyl)retinamide and N-4-carboxyphenylretinamide.

The term “cytotoxics” in the course of the present invention refers tocompounds that primarily trigger cell death through direct action oncell function(s) or which interfere with or inhibit cell myosis, such asalkylating agents, tumor necrosis factors, intercalating agents,microtubule inhibitors and topoisomerase inhibitors. Non-limitingexamples of cytotoxics are tirapazimin, sertenef, cachectine,ifosfamide, tasonermine, lonidamine, carboplatin, altretamine,prednimustine, dibromodulcit, ranimustine, fotemustine, nedaplatin,oxaliplatin, temozolomide, heptaplatin, estramustin,improsulfan-tosylate, trofosfamide, nimustine, dibrospidium-chloride,pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,dexifosfamide, cis-amindichloro(2-methylpyridine)platin, benzylguanine,glufosfamide, GPX100,(trans,trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platin(II)]bis-[diamine(chloro)platin(II)]-tetrachloride,diarizidinylspermine, arsenium trioxide,1-(11-Dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantren, mitoxantron, pirarubicin, pinafide,valrubicine, amrubicine, antineoplaston,3′-desamino-3′-morpholino-13-desoxo-10-hydroxycaminomycin, annamycin,galarubicin, elinafide, MEN10755 and4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (WO00/50032).

Non-limiting examples of microtubule inhibitors are paclitaxel,vindesine-sulfate, 3′,4′-dideshydro-4′-desoxy-8′-norvincaleukoblastine,docetaxol, rhizoxine, dolastatine, mivobuline-isethionate, auristatine,cemadotine, RPR109881, BMS184476, vinflunine, cryptophycine,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)-benzenesulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258 and BMS188797.

Non-limiting examples of topoisomerase inhibitors are topotecane,hycaptamine, irinotecane, rubitecane,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusine,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo-[de]-pyrano-[3′,4′:b,7]indolizino[1,2b]quiinoline-10,13(9H,15H)-dione,lurtotecane, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecine, BNP1350,BNPI1100, BN80915, BN80942, etoposide-phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-desoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylendioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium,6,9-bis[(2-aminoethyl)amino]-benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]-acridine-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxane-then-4-ylmethyl]formamide,N-(2-(dimethyl-amino)-ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)-ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-oneand dimesna.

Non-limiting examples of antiproliferative agents are antisense RNA- andantisense-DNA oligonucleotides, such as G3139, ODN698, RVASKRAS, GEM231and INX3001, as well as antimetabolites such as enocitabine, carmofur,tegafur, pentostatine, doxifluridine, trimetrexate, fludarabine,capecitabine, galocitabine, cytarabin-ocfosfate, fosteabinesodiumhydrate, raltitrexed, paltitrexide, emitefur, tiazofurine,decitabine, nolatrexed, pemetrexed, nelzarabine,2′-desoxy-2′-methylidencytidine, 2′-fluoromethylen-2′-desoxycytidine,N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-desoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidine, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazine-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutaminicacid, aminopterine, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diaza-tetracyclo-(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylaceticacid ester, swainsonine, lometrexole, dexrazoxane, methioninase,2′-cyan-2′-desoxy-N4-palmitoyl-1-B-D-arabinofuranosylcytosine and3-aminopyridine-2-carboxaldehyde-thiosemicarbazone.

“Antiproliferative agents” also comprises monoclonal antibodies againstgrowth factors that have not been listed under “angiogenesisinhibitors”, such as trastuzumab, as well as tumor suppressor genes,such as p53.

In another aspect of the invention, a medicament according to aboveaspects and embodiments is provided, wherein in such medicamentcomprises at least one additional pharmacologically active substance(drug, ingredient).

In a preferred embodiment the at least one pharmacologically activesubstance is a substance as described herein.

In another aspect of the invention, a medicament according to aboveaspects and embodiments is provided, wherein the medicament is appliedbefore and/or during and/or after treatment with at least one additionalpharmacologically active substance.

In a preferred embodiment the at least one pharmacologically activesubstance is a substance as described herein.

In another aspect of the invention, a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof the invention is provided.

In a preferred embodiment, the pharmaceutical composition contains atleast one additional compound selected from the group consisting ofphysiologically acceptable excipients, auxiliaries, adjuvants, diluents,carriers and/or additional pharmaceutically active substance other thanthe compounds of the invention.

In another aspect of the invention, a pharmaceutical composition isdisclosed which comprises at least one compound of the invention, atleast one pharmacologically active substance other than the compounds ofthe invention as described herein; and a pharmaceutically acceptablecarrier.

A further embodiment of the present invention is a process for themanufacture of said pharmaceutical compositions, characterized in thatone or more compounds according to the invention and one or morecompounds selected from the group consisting of solid, liquid orsemiliquid excipients, auxiliaries, adjuvants, diluents, carriers andpharmaceutically active agents other than the compounds according to theinvention, are converted in a suitable dosage form.

In another aspect of the invention, a kit is provided comprising atherapeutically effective amount of at least one compound of theinvention and/or at least one pharmaceutical composition as describedherein and a therapeutically effective amount of at least one furtherpharmacologically active substance other than the compounds of theinvention.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by oral, parenteral, topical, enteral,intravenous, intramuscular, inhalant, nasal, intraarticular,intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal,transdermal, or buccal routes. Alternatively, or concurrently,administration may be by the oral route. The dosage administered will bedependent upon the age, health, and weight of the recipient, kind ofconcurrent treatment, if any, frequency of treatment, and the nature ofthe effect desired. Parenteral administration is preferred. Oraladministration is especially preferred.

Suitable dosage forms include, but are not limited to capsules, tablets,pellets, dragees, semi-solids, powders, granules, suppositories,ointments, creams, lotions, inhalants, injections, cataplasms, gels,tapes, eye drops, solution, syrups, aerosols, suspension, emulsion,which can be produced according to methods known in the art, for exampleas described below:

tablets: mixing of active ingredient/s and auxiliaries, compression ofsaid mixture into tablets (direct compression), optionally granulationof part of mixture before compression.

capsules: mixing of active ingredient/s and auxiliaries to obtain aflowable powder, optionally granulating powder, fillingpowders/granulate into opened capsules, capping of capsules.

semi-solids (ointments, gels, creams): dissolving/dispersing activeingredient/s in an aqueous or fatty carrier; subsequent mixing ofaqueous/fatty phase with complementary fatty/aqueous phase,homogenization (creams only).

suppositories (rectal and vaginal): dissolving/dispersing activeingredient/s in carrier material liquified by heat (rectal: carriermaterial normally a wax; vaginal: carrier normally a heated solution ofa gelling agent), casting said mixture into suppository forms, annealingand withdrawal suppositories from the forms.

aerosols: dispersing/dissolving active agent/s in a propellant, bottlingsaid mixture into an atomizer.

In general, non-chemical routes for the production of pharmaceuticalcompositions and/or pharmaceutical preparations comprise processingsteps on suitable mechanical means known in the art that transfer one ormore compounds of the invention into a dosage form suitable foradministration to a patient in need of such a treatment. Usually, thetransfer of one or more compounds of the invention into such a dosageform comprises the addition of one or more compounds, selected from thegroup consisting of carriers, excipients, auxiliaries and pharmaceuticalactive ingredients other than the compounds of the invention. Suitableprocessing steps include, but are not limited to combining, milling,mixing, granulating, dissolving, dispersing, homogenizing, castingand/or compressing the respective active and non-active ingredients.Mechanical means for performing said processing steps are known in theart, for example from Ullmann's Encyclopedia of Industrial Chemistry,5th Edition. In this respect, active ingredients are preferably at leastone compound of the invention and one or more additional compounds otherthan the compounds of the invention, which show valuable pharmaceuticalproperties, preferably those pharmaceutical active agents other than thecompounds of the invention, which are disclosed herein.

Particularly suitable for oral use are tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal use are suppositories, suitable for parenteral use are solutions,preferably oil-based or aqueous solutions, furthermore suspensions,emulsions or implants, and suitable for topical use are ointments,creams or powders. The compounds of the invention may also belyophilised and the resultant lyophilisates used, for example, for thepreparation of injection preparations. The preparations indicated may besterilised and/or comprise assistants, such as lubricants,preservatives, stabilisers and/or wetting agents, emulsifiers, salts formodifying the osmotic pressure, buffer substances, dyes, flavours and/ora plurality of further active ingredients, for example one or morevitamins.

Suitable excipients are organic or inorganic substances, which aresuitable for enteral (for example oral), parenteral or topicaladministration and do not react with the compounds of the invention, forexample water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, suchas lactose, sucrose, mannitol, sorbitol or starch (maize starch, wheatstarch, rice starch, potato starch), cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, magnesium stearate, talc, gelatine, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose,polyvinyl pyrrolidone and/or vaseline.

If desired, disintegrating agents may be added such as theabove-mentioned starches and also carboxymethyl-starch, cross-linkedpolyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such assodium alginate. Auxiliaries include, without limitation,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings, which, if desired, are resistant to gastric juices.For this purpose, concentrated saccharide solutions may be used, whichmay optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices or to provide a dosage formaffording the advantage of prolonged action, the tablet, dragee or pillcan comprise an inner dosage and an outer dosage component me latterbeing in the form of an envelope over the former. The two components canbe separated by an enteric layer, which serves to resist disintegrationin the stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, acetyl alcohol, solutions of suitable cellulose preparationssuch as acetyl-cellulose phthalate, cellulose acetate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Suitable carrier substances are organic or inorganic substances whichare suitable for enteral (e.g. oral) or parenteral administration ortopical application and do not react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, polyethylene glycols,gelatin, carbohydrates such as lactose or starch, magnesium stearate,talc and petroleum jelly. In particular, tablets, coated tablets,capsules, syrups, suspensions, drops or suppositories are used forenteral administration, solutions, preferably oily or aqueous solutions,furthermore suspensions, emulsions or implants, are used for parenteraladministration, and ointments, creams or powders are used for topicalapplication. The compounds of the invention can also be lyophilized andthe lyophilizates obtained can be used, for example, for the productionof injection preparations.

The preparations indicated can be sterilized and/or can containexcipients such as lubricants, preservatives, stabilizers and/or wettingagents, emulsifiers, salts for affecting the osmotic pressure, buffersubstances, colorants, flavourings and/or aromatizers. They can, ifdesired, also contain one or more further active compounds, e.g. one ormore vitamins.

Other pharmaceutical preparations, which can be used orally includepush-fit capsules made of gelatine, as well as soft, sealed capsulesmade of gelatine and a plasticizer such as glycerol or sorbitol. Thepush-fit capsules can contain the active compounds in the form ofgranules, which may be mixed with fillers such as lactose, binders suchas starches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as fattyoils, or liquid paraffin. In addition, stabilizers may be added.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally include aqueoussolutions, suitably flavoured syrups, aqueous or oil suspensions, andflavoured emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil or peanut oil, as well as elixirs and similar pharmaceuticalvehicles. Suitable dispersing or suspending agents for aqueoussuspensions include synthetic and natural gums such as tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatine.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400).

Aqueous injection suspensions may contain substances, which increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran, optionally, thesuspension may also contain stabilizers.

For administration as an inhalation spray, it is possible to use spraysin which the active ingredient is either dissolved or suspended in apropellant gas or propellant gas mixture (for example CO₂ orchlorofluorocarbons). The active ingredient is advantageously used herein micronized form, in which case one or more additional physiologicallyacceptable solvents may be present, for example ethanol. Inhalationsolutions can be administered with the aid of conventional inhalers.

Possible pharmaceutical preparations, which can be used rectallyinclude, for example, suppositories, which consist of a combination ofone or more of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatine rectal capsules, which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

For use in medicine, the compounds of the present invention will be inthe form of pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds of the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts; alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic bases, e.g. quaternaryammonium salts.

The pharmaceutical preparations can be employed as medicaments in humanand veterinary medicine. As used herein, the term “effective amount”means that amount of a drug or pharmaceutical agent that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought, for instance, by a researcher or clinician.Furthermore, the term “therapeutically effective amount” means anyamount which, as compared to a corresponding subject who has notreceived such amount, results in improved treatment, healing,prevention, or amelioration of a disease, disorder, or side effect, or adecrease in the rate of advancement of a disease or disorder. The termalso includes within its scope amounts effective to enhance normalphysiological function. Said therapeutic effective amount of one or moreof the compounds of the invention is known to the skilled artisan or canbe easily determined by standard methods known in the art.

The compounds of the invention and the additional active substances aregenerally administered analogously to commercial preparations. Usually,suitable doses that are therapeutically effective lie in the rangebetween 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500 mgand especially between 0.5 mg and 100 mg per dose unit. The daily doseis preferably between about 0.001 mg/kg and 10 mg/kg of body weight.

Those of skill will readily appreciate that dose levels can vary as afunction of the specific compound, the severity of the symptoms and thesusceptibility of the subject to side effects. Some of the specificcompounds are more potent than others. Preferred dosages for a givencompound are readily determinable by those of skill in the art by avariety of means. A preferred means is to measure the physiologicalpotency of a given compound.

For the purpose of the present invention, all mammalian species areregarded as being comprised. In a preferred embodiment, such mammals areselected from the group consisting of “primate, human, rodent, equine,bovine, canine, feline, domestic animals, cattle, livestock, pets, cow,sheep, pig, goat, horse, pony, donkey, hinny, mule, hare, rabbit, cat,dog, guinea pig, hamster, rat, mouse”. More preferably, such mammals arehumans. Animal models are of interest for experimental investigations,providing a model for treatment of human diseases.

The specific dose for the individual patient depends, however, on themultitude of factors, for example on the efficacy of the specificcompounds employed, on the age, body weight, general state of health,the sex, the kind of diet, on the time and route of administration, onthe excretion rate, the kind of administration and the dosage form to beadministered, the pharmaceutical combination and severity of theparticular disorder to which the therapy relates. The specifictherapeutic effective dose for the individual patient can readily bedetermined by routine experimentation, for example by the doctor orphysician, which advises or attends the therapeutic treatment.

In the case of many disorders, the susceptibility of a particular cellto treatment with the subject compounds may be determined by in vitrotesting. Typically a culture of the cell is combined with a subjectcompound at varying concentrations for a period of time sufficient toallow the active agents to show a relevant reaction, usually betweenabout one hour and one week. For in vitro testing, cultured cells from abiopsy sample may be used.

Even without further details, it is assumed that a person skilled in theart will be able to utilise the above description in the broadest scope.The preferred embodiments should therefore merely be regarded asdescriptive disclosure, which is absolutely not limiting in any way.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means that, if necessary, the solventis removed, water is added if necessary, the pH is adjusted, ifnecessary, to between 2 and 10, depending on the constitution of the endproduct, the mixture is extracted with ethyl acetate or dichloromethane,the phases are separated, the organic phase is washed with saturatedNaHCO₃ solution, if desired with water and saturated NaCl solution, isdried over sodium sulfate, filtered and evaporated, and the product ispurified by chromatography on silica gel, by preparative HPLC and/or bycrystallisation. The purified compounds are, if desired, freeze-dried.

Mass spectrometry (MS): ESI (electrospray ionisation) (M+H)⁺

LIST OF ABBREVIATIONS AND ACRONYMS

AcOH acetic acid, anh anhydrous, atm atmosphere(s), BOCtert-butoxycarbonyl CDI 1,1′-carbonyl diimidazole, conc concentrated, dday(s), dec decomposition, DMAC N,N-dimethylacetamide, DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(IH)-pyrimidinone, DMFNN-dimethylformamide, DMSO dimethylsulfoxide, DPPA diphenylphosphorylazide, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, EtOAc ethylacetate, EtOH ethanol (100%), Et₂O diethyl ether, Et₃N triethylamine, hhour(s), MeOH methanol, pet. ether petroleum ether (boiling range 30-60°C.), temp. temperature, THF tetrahydrofuran, TFA trifluoroAcOH, Tftrifluoromethanesulfonyl.

The contents of all cited references are hereby incorporated byreference in their entirety. The invention is explained in more detailby means of the following examples without, however, being restrictedthereto.

EXAMPLES I. Synthesis of Selected Compounds of the Invention

The following compounds were synthesized and characterized. However, itlies in the knowledge of a person skilled in the art to prepare andcharacterize these compounds differently.

Example 1 Synthesis of6-(1H-Benzotriazole-5-carbonyl)-2-[3-(4-chloro-phenyl)-ureido]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylicacid amide 6

a. Synthesis of2-Amino-3-carbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylicacid tert-butyl ester (3)

Starting material 1 (25 g, 125 mmol) was suspended in a 250 ml bowlflask in 125 ml abs. ethanol and mixed with starting material 2 (10.5 g,125 mmol) and sulfur (4.023 g, 125 mmol). 12.9 ml (125 mmol) diethylamine was added dropwise to the yellow suspension, which thereby becameof orange color. The reaction mixture was stirred over night at ambienttemperature. Next day, the reddish solution was concentrated in vacuoand the crude product was re-crystallized in methanol. The desiredproduct 3 was isolated as a red-brown solid (40.7 g, 116 mmol, 93%).

b. Synthesis of3-Carbamoyl-2-[3-(4-chloro-phenyl)-ureido]-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylicacid tert-butyl ester (4)

Compound 3 (1.5 g, 4.3 mmol) and p-Chlorphenylisocyanat (724 mg, 4.7mmol) were dissolved in pyridine (12 ml) and stirred over night at roomtemperature. Another equivalent of isocyanate (724 mg, 4.7 mmol) wasadded and the mixture was stirred over the weekend. The solvent wasreduced under vacuum and the crude product (2.3 g, 4 mmol; light brownsolid) was used in the next reaction without further purification(Content: 79% compound 4 according to UV).

c. Synthesis of2-[3-(4-Chloro-phenyl)-ureido]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylicacid amide (5)

Starting material 4 (2.3 g, 4.1 mmol) was suspended in 20 ml DCM andmixed with trifluoro acetic acid (TFA, 7.9 ml, 102 mmol). The resultingbrown solution was stirred at room temperature for 50 Min. the solventwas reduced in vacuo and the crude product was purified by prep. HPLC(Method 1).

The product fraction were merged and the solvent was reduced and theproduct finally lyophilized yielding 5 (850 mg, 2.4 mmol, 59%) as alight brown solid.

d. Synthesis of6-(1H-Benzotriazole-5-carbonyl)-2-[3-(4-chloro-phenyl)-ureido]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylicacid amide (6)

Starting material 5 (847 mg, 2.4 mmol) was suspended in DMF (8 ml) and1H-1,2,3-benzothiazole-5-carboxyllic acid (473 mg, 2.9 mmol), dry HOBt(427 mg, 2.9 mmol) and EDCI (606 mg, 2.9 mmol) were added. The brownsuspension was stirred at ambient temperature over the weekend. As thereaction was not complete yet, the reaction was further stirred at 80°for 4 h. Thereby a brown solution was formed. The solvent was evaporatedin vacuo and the crude product was further purified by prep. HPLC(Method 1). The product fractions were merged, the solvent wasevaporated and the product lyophilized. Thereby 310 mg of the desiredproduct 6 (0.635 mmol, 28%) were isolated as a light brown solid andadditional 58 mg of the same product with 76% content which could havebeen purified further.

As an alternative, 5 can be prepared by using an alloc-protectedstarting material instead of the BOC-protected one:

e. Synthesis of2-Amino-3-carbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylicacid allyl ester (8)

Starting materials 7 (4 g, 22 mmol), 2 (1.8 g, 22 mmol) and sulfur (700mg, 22 mmol) were weighed into a bowl flask and 16 ml of ethanol wereadded. Diethyl amine (2.2 ml, 22 mmol) was added dropwise to the yellowsuspension. The reaction was stirred over night. The orange coloredprecipitate was filtered off and identified as the product 8 (4 g, 11.8mmol, 83% content, 54% yield) which could be used without furtherpurification.

f. Synthesis of3-Carbamoyl-2-[3-(4-chloro-phenyl)-ureido]-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylicacid allyl ester (9)

Starting material 8 (1 g, 3.6 mmol) was dissolved in 12 ml of pyridineand p-chlorphenyl isocyanate (546 mg, 3.6 mmol) was added. The redsolution was stirred over the weekend. The solvent was reduced in avacuum centrifuge. The crude product was used without furtherpurification (green-brown solid, 1.13 g, 65% content 9, 46% yield).

g. Synthesis of2-[3-(4-Chloro-phenyl)-ureido]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylicacid amide (5)

Starting material 9 (750 mg, 1.7 mmol) was dissolved under Nitrogenatmosphere in 10 ml DCM in a 2 necked flask and a solution of morpholine(3 ml, 34.5 mmol) in 34.5 ml DCM was added. The solution was stirred for5 Min. then a solution of Tetrakis(triphenylphosphin)-palladium(0) (199mg, 0.2 mmol) in 17.2 ml DCM was added. After about 8 Min a brownsuspension was formed. The reaction was stirred at ambient temperaturefor another 40 Min. The solvent was then reduced and product 5 wasthereby isolated in two fractions: very pure as white crystals (246 mg,0.7 mmol, 41%) and with 56% content in a brown solid (250 mg, 56% Gehaltan 5, 0.4 mmol), which contained side products as well but could bepurified by prep. HPLC (Method 2). The pure product fractions weremerged, the solvent reduced and the product lyophilized.

As an alternative, as exemplified in example 2, the final products canbe prepared without the use of any protecting group:

Example 2 Synthesis of1-[6-(1H-Benzotriazole-5-carbonyl)-3-(pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-(4-chloro-phenyl)-urea(14)

a. Synthesis of(2-Amino-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-3-yl)-pyrrolidin-1-yl-methanone(12)

In a 100 ml bowl flask with dropping funnel, pyridon-(4) (startingmaterial 10, 1 g, 10.1 mmol) was dissolved in 50 ml abs. ethanol. Thenstarting material 11 (1.4 g, 10.1 mmol) and sulfur (0.3 g, 10.1 mmol)were added. 2 ml diethyl amine (20.2 mmol) were added dropwise to theyellow suspension (over 20 Min) resulting in a brown solution. Thereaction was stirred at room temperature over night. Another ml ofDiethyl amine (10.1 mmol) was added and the reaction was stirred foranother 7 h. The reaction was concentrated in vacuo. Thereby the desiredproduct 12 was isolated as a viscous brown matter (3.2 g, 75% content of12, 95% yield), which could be used without further purification.

b. Synthesis of[2-Amino-6-(1H-benzotriazole-5-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-3-yl]-pyrrolidin-1-yl-methanone(13)

Starting material 12 (1.6 g, 6.4 mmol) was dissolved in 20 ml DMF. ThenEDCI (1.46 g, 7.6 mmol) and HOBt (1.3 g, 9.5 mmol) were added. Now, onehalf of 1.04 g (6.4 mmol) 1H-1,2,3-benzothiazole-5-carboxyllic acid wasadded. The reaction mixture was stirred at ambient temperature overnight. Then the other half of the 1H-1,2,3-benzothiazole-5-carboxyllicacid was added and the reaction mixture was again stirred at ambienttemperature over night. The reaction mixture was now concentrated invacuo yielding 7 g crude product. Those were taken up in ethyl acetateand water and the phases were separated. The organic phase was washedwith water and the combined aqueous phases were washed with ethylacetate. The combined organic phases were washed with brine, dried overMgSO₄ and concentrated in vacuo. The desired product 13 was isolated asa brown oil (1.2 g, 20% content, 10% yield).

c. Synthesis of1-[6-(1H-Benzotriazole-5-carbonyl)-3-(pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-(4-chloro-phenyl)-urea(14)

Starting material 13 (1.2 g, 20% content, 0.6 mmol) was dissolved in 5ml pyridine and one half of 112 mg (0.7 mmol) p-chlorphenyl isocyanatewas added. The reaction mixture was stirred over night at ambienttemperature. Then the other half of the p-chlorphenyl isocyanate wasadded and the reaction was again stirred over night at ambienttemperature. The reaction was now concentrated in vacuo and the therebyisolated crude product was dissolved in 7 ml DMSO and purified by prep.HPLC (Method 3). The pure fractions were combined, the solvent reducedand the product finally lyophilized. The desired product 14 couldthereby be isolated as yellow solid (16.2 mg, 4%; and additional 17 mg,84% content 14, 4% yield).

In analogy to example 2-a, pyridon(4)-hydrochloride (15) was reactedwith cyano-acetic acid methyl ester (16):

a.′ Synthesis of2-Amino-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acidmethyl ester hydrochloride (17)

Piperidone-(4), hydrochloride (15, 154 g, 1.1 mol), Methyl-cyanacetat(16, 84 g, 0.8 mol) and sulfur (32 g, 1 mol) were suspended in 500 mlmethanol. Then diethyl amine (150 ml, 1.4 mol) was added. The mixturewas stirred at room temperature for 5 h. The resulting crystals werefiltered, washed with a mixture of iso-propanol and methanol and dried.The mother liquor was reduced to 50% volume in vacuo and left overnight. The resulting crystals were again filtered, washed withiso-propanol and dried. In total 133 g of the desired product 17 (0.54mol, 47%) were isolated, characterized by NMR and further used inreactions in analogy to 12.

Instead of ureas also amides were synthesized:

Example 3 Synthesis of6-(1H-Benzotriazole-5-carbonyl)-2-[2-(4-chloro-2-fluoro-phenyl)-acetylamino]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylicacid amide

a. Synthesis of3-Carbamoyl-2-[2-(4-chloro-2-fluoro-phenyl)-acetylamino]-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylicacid tert-butyl ester (19)

Starting material 3 (1 g, 2.9 mmol) was suspended in 11 ml DMF andstarting material 18 (593 mg, 3.1 mmol), dry HOBt (505 mg, 3.1 mmol) andEDCI (657 mg, 3.4 mmol) were added. The brown suspension was stirredover the weekend at ambient temperature then the reaction was heated to80° C. over night. The solvent was reduced in the vacuum centrifuge andthe crude product (a brown oil) was used without further purification(3.2 g, 22% content 19, 53% yield).

b. Synthesis of2-[2-(4-Chloro-2-fluoro-phenyl)-acetylamino]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylicacid amide (20)

Starting material 19 (3.2 g, 22% content, 1.5 mmol) was dissolved in 25ml dried DCM and trifluoro acetic acid (TFA, 8.0 ml, 104 mmol) wasadded. The reaction was stirred at ambient temperature for 30 Min. Thesolvent was reduced in vacuo and the crude product was purified at theFlashmaster (Method 1). The isolated product was not sufficiently pureand was therefore purified again at the prep. HPLC (Method 4). The purefractions were combined and the solvent was reduced. The desired product20 was thereby isolated as a brown solid (236 mg, 42%).

c. Synthesis of6-(1H-Benzotriazole-5-carbonyl)-2-[2-(4-chloro-2-fluoro-phenyl)-acetylamino]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylicacid amide (21)

Starting material 20 (118 mg, 0.3 mmol) was suspended in 2 ml dry DMFand 1H-1,2,3-benzothiazole-5-carboxyllic acid (63 mg, 0.4 mmol, 1.2equiv.), dry HOBt (52 mg, 0.4 mmol) and EDCI (74 mg, 0.4 mmol) wereadded. The brown suspension was stirred at 80° C. over night. Thenanother 0.5 equiv. 1H-1,2,3-benzothiazole-5-carboxyllic acid were addedand the reaction was stirred another 6 h at 80° C. the solvent wasreduced under vacuo and the remaining crude product further purified byprep. HPLC (Method 3). The pure fractions were combined and the solventwas reduced. The remaining product was lyophilized yielding the desiredproducts 21 as a light-brown solid (20 mg, 0.04 mmol, 12%).

Analogously, instead of making amides with1H-1,2,3-benzothiazole-5-carboxylic acid other substituents wereintroduced as well:

Example 4 Synthesis of2-[2-(4-Chloro-2-fluoro-phenyl)-acetylamino]-6-pyridin-4-ylmethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylicacid amide (23)

Synthesis of2-[2-(4-Chloro-2-fluoro-phenyl)-acetylamino]-6-pyridin-4-ylmethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylicacid amide (23)

Amine 20 (168 mg, 0.5 mmol) and aldehyde 22 (0.1 ml, 0.5 mmol) weredissolved in 1,2-Dichloroethan (5 ml) and dry THF (5 ml). 51 μl glacialacetic acid (0.9 mmol) were added and the suspension was stirred for 3 hat ambient temperature. Now 305 mg NaB(OAc)₃ (1.4 mmol) and another 51μl glacial acetic acid (0.9 mmol) were added and the reaction wasstirred at room temperature over night. The resulting solid was filteredoff. The mother liquid contained the product and was thus concentratedyielding 400 mg crude product which was further purified by prep. HPLC(Method 4). 26 mg of the desired product 23 were isolated as brownamorphous solid (12%).

Example 5 Synthesis of2-[3-(4-Chloro-phenyl)-ureido]-1H-indole-3,6-dicarboxylic acid 3-amide6-[(2-oxo-2,3-dihydro-benzooxazol-6-yl)-amide] (32)

a. Synthesis of 4-Fluoro-3-nitro-benzoic acid methyl ester (25)

Starting material 24 (10 g, 54 mmol) was placed in 60 ml methanol and0.5 ml sulfuric acid was added dropwise. Now the reaction was stirredover night at 80° C. The reaction mixture was then distributed betweenwater and ethyl acetate. The combined organic phases were dried overMgSO₄, filtered and concentrated yielding the desired product 25quantitatively as amorphous solid (10.8 g, 54 mmol).

b. Synthesis of 4-(Carbamoyl-cyano-methyl)-3-nitro-benzoic acid methylester (27)

Starting material 25 (10 g, 50 mmol) and cyanacetamide (26, 8.4 g, 100mmol) were dissolved in dry THF and NaH (60% ig, 4 g, 100 mmol) wasadded. The reaction was stirred over night at ambient temperature. Nowit was cooled to 0° C. and 4 N HCl/Dioxan was added. The reactionmixture was concentrated in vacuo, the solid residue crystallized with400 ml isopropyl ethyl ether, resulting crystals were filtered anddried. Then the crystals were washed with water and again filtered anddried. Thereby 8.9 g of the desired product 27 (67%, 34 mmol) wereisolated.

c. Synthesis of 4-Fluoro-3-amino-benzoic acid methyl ester (28)

Starting material 27 (7 g, 26.6 mmol) was dissolved in 700 ml methanol.The solution was hydrogenated in tow batches in the H-cube (ThalesNanotechnology).

Parameters:

flow rate: 3.0 ml/min

mode full H₂

catalyst Raney Nickel THS 01122

T/° C. R.T.

p/bars ambient pressure

The hydrogenated solutions were combined and reduced in vacuo. Theproduct isolated thereby (28, 5.5 g, 23.5 mmol, 89%) was used furtherwithout additional purification.

d. Synthesis of 2-Amino-3-carbamoyl-1H-indole-6-carboxylic acid (29)

Starting material 28 (5.5 g, 23.5 mmol) was dissolved in 200 ml abs. THFand 2 N NaOH (45 ml, 90 mmol) was added at room temperature. Uponstirring, the solution got dark and a solid precipitate was formed. Thesuspension was reduced to about 100 ml and extracted three times with400 ml ethyl acetate each. The aqueous phase was reduced in vacuo andtreated twice with ethyl acetate upon which the desired product 29 wascrystallized (1.1 g, 5.5 mmol, 21%).

e. Synthesis of 2-Amino-1H-indole-3,6-dicarboxylic acid 3-amide6-[(2-oxo-2,3-dihydro-benzooxazol-6-yl)-amide] (31)

Starting material 29 (500 mg, 2.3 mmol) was dissolved in 2 ml dry DMF.Then EDCI (575 mg, 3 mmol) and HOBt (322 mg, 2.4 mmol) were added. Thereaction was stirred over night at ambient temperature. Now the reactionmixture was poured into water and the resulting precipitate was filteredand dried. This intermediate was identified to be the HOBT ester of thestarting material 29 (645 mg, 1.9 mmol, 84%), which could be usedwithout further purification:

500 mg (1.5 mmol) of the intermediate and 300.3 mg (2 mmol)6-Amino-3H-benzooxazol-2-one (preparation see below) were dissolved indry DMF (2 ml). Then 383 mg (2 mmol) EDCI were added and the reactionwas stirred at 60° C. over night. Now the solution was added to waterand the resulting dark precipitate was filtered and dried yielding 400mg (0.85 mmol) of the desired product 31 in 43% yield (calculated fromthe used intermediate).

f. Synthesis of2-[3-(4-Chloro-phenyl)-ureido]-1H-indole-3,6-dicarboxylic acid 3-amide6-[(2-oxo-2,3-dihydro-benzooxazol-6-yl)-amide] (32)

Starting material 31 (100 mg, 0.3 mmol) was dissolved in 1 ml drypyridine. 4-Chlorphenyl isocyanate (46 mg, 0.3 mmol) was then added andthe mixture stirred at ambient temperature. Then another 40 mg (0.29mmol) 4-Chlorphenyl isocyanate were added and the reaction was stirredat 50° C. After a few hours the reaction was reduced in vacuo andpurified by prep. HPLC. After concentration of the pure fractions 10 mg(0.02 mmol, 7%) of the desired product 32 were isolated.

g. Synthesis of 6-Amino-3H-benzooxazol-2-one (30)

5 g (26.9 mmol) 6-Nitrobenoxazol-2(3H)-on were dissolved in 100 ml THFand 1 g Pd—C-5% (containing 50.5% water) were added. The reaction washydrogenated with H2 over 16 h. The reaction mixture was then filteredover celite and reduced in vacuo. Thereby the desired product 30 wasisolated as a red-brown solid (2.6 g, 17.4 mmol, 65%).

Example 6 Synthesis of2-[3-(4-Chloro-phenyl)-ureido]-benzothiazole-6-carboxylic acid(2-oxo-2,3-dihydro-benzooxazol-6-yl)-amide (36)

a. Synthesis of2-[3-(4-Chloro-phenyl)-ureido]-benzothiazole-6-carboxylic acid ethylester (34)

Starting material 33 (400 mg, 1.8 mmol) was dissolved in dry pyridine (1ml). 4-Chlorphenylisocyanat (307 mg, 2 mmol) was added and the reactionwas stirred at ambient temperature over night. The reaction mixture wasthen added to 1 N HCl and the resulting precipitate was filtered, washedwith water and dried. The desired product 36 was thus isolated (710 mg,1.58 mmol, 88%).

b. Synthesis of2-[3-(4-Chloro-phenyl)-ureido]-benzothiazole-6-carboxylic acid (35)

505 mg (4.5 mmol) potassium-tert-butylat was placed in a bowl flask and90 ml water were added, yielding finely dispersed KOH. Starting material34 (710 mg, 1.6 mmol) was added to this suspension and the mixture wasstirred at ambient temperature. After 3 h the reaction was heated to 60°C. over night. Then 4.5 ml 1 N HCl were added to the suspension and themixture was concentrated in vacuo yielding a solid. Thereby the desiredproduct 35 was isolated as a mixture with NaCl (800 mg, 45% content,1.035 mmol, 65% yield) which could be used without further purification.

c. Synthesis of2-[3-(4-Chloro-phenyl)-ureido]-benzothiazole-6-carboxylic acid(2-oxo-2,3-dihydro-benzooxazol-6-yl)-amide (36)

Starting material 35 (300 mg, 45% content, 0.4 mmol) and6-Amino-3H-benzooxazol-2-one (30, 58 mg, 0.4 mmol) were dissolved in 2ml of dry DMF. Then EDCI (96 mg, 0.5 mmol) and HOBt (76 mg, 0.5 mmol)were added. The reaction was stirred at ambient temperature over night.It was then purred into water and the resulting precipitate wasfiltered. The isolated precipitate was then stirred in 100 ml warmmethanol and the non-soluble crystals filtered and washed with methanol.Thereby the desired product 36 (130 mg, 0.271 mmol, 70%) could beisolated.

Example 7 Synthesis of2-[2-(4-Chloro-2-fluoro-phenyl)-acetylamino]-benzothiazole-6-carboxylicacid (2-oxo-2,3-dihydro-benzooxazol-6-yl)-amide (38)

a. Synthesis of2-[2-(4-Chloro-2-fluoro-phenyl)-acetylamino]-benzothiazole-6-carboxylicacid (37)

Starting material 18 (100 mg, 0.5 mmol) was dissolved in 2 ml DMF. NowEDCI (125 mg, 0.7 mmol) and HOBt (99 mg, 0.7 mmol) were added. Afterstirring 3 h at room temperature, starting material 33 (103 mg, 0.5mmol) was added and the reaction was stirred 48 h at room temperature.The solution was poured into 1 N HCl and the resulting precipitate wasfiltered and dried yielding the desired product 37 (60 mg, 0.2 mmol, 70%content, 31% yield).

b. Synthesis of2-[2-(4-Chloro-2-fluoro-phenyl)-acetylamino]-benzothiazole-6-carboxylicacid (2-oxo-2,3-dihydro-benzooxazol-6-yl)-amide (38)

Starting material 37 (60 mg, 0.2 mmol, 70% content) and6-Amino-3H-benzooxazol-2-one (30, 25 mg, 0.2 mmol) were dissolved in 2ml DMF. Then EDCI (38 mg, 0.2 mmol) and HOBt (31 mg, 0.2 mmol) wereadded. The reaction was stirred over night at ambient temperature,concentrated in vacuo and purified by prep HPLC (Method 1). Byconcentration of the pure fractions the desired product 38 (23 mg, 0.04mmol, 24%) could be isolated.

Example 8 Synthesis of6-(1H-Benzotriazole-5-carbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylicacid [2-(4-chloro-phenyl)-ethyl]-amide (43)

a. Synthesis of6-(1H-Benzotriazole-5-carbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylicacid ethyl ester (40)

Starting material 39 (1.7 g, 6.4 mmol), 4-methyl morpholine (700 μL, 6.4mmol) and 1H-1,2,3-benzothiazole-5-carboxyllic acid (1 g, 6.4 mmol) weredissolved in 15 ml DMF. Then EDCI (1.2 g, 6.4 mmol) and HOBt (0.9 g, 6.4mmol) were added. The reaction was stirred over night at ambienttemperature. Then water was added to the reaction mixture and stirringwas continued. As no precipitate was formed, ethyl acetate was added andthe phases were separated. The aqueous phase was washed twice with ethylacetate. The combined organic phases were dried over Na₂SO₄, filteredand concentrated in vacuo.

The desired product 40 was isolated quantitatively (2.6 g, 6.4 mmol) andfurther used without purification.

b. Synthesis of6-(1H-Benzotriazole-5-carbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylicacid (41)

Starting material 40 (2.6 g, 6.4 mmol) was mixed with 2 N NaOH (15 ml)and ethanol (15 ml) and stirred at ambient temperature. Additional 15 ml2 N NaOH were added. After the reaction was completed, the mixture wasreduced to dryness, the solid was dissolved in water, adjusted to pH 2with 2N HCl and the resulting precipitate was filtered and dried. Thusthe desired product 41 (1.4 g, 4.4 mmol, 57%) could be isolated assolid.

c. Synthesis of6-(1H-Benzotriazole-5-carbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylicacid [2-(4-chloro-phenyl)-ethyl]-amide (43)

Starting material 41 (171.3 mg, 0.5 mmol), 4-Methylmorpholin (60.3 μL,0.5 mmol) and starting material 42 (85 mg, 0.5 mmol) were dissolved in 5ml DMF. Then EDCI (105 mg, 0.5 mmol) and HOBt (74 mg, 0.5 mmol) wereadded. The reaction was stirred over night at ambient temperature.

The reaction mixture was poured into water and the resulting precipitatewas filtered off. It was stirred in methyl tert-butyl ether and againfiltered. Further purification was done by chromatography with a“Companion” (Method 1).

The pure fractions were concentrated, stirred in methyl tert-butyl etherand filtered. The desired product 43 could thereby be isolated (45.6 mg,0.1 mmol, 18%).

Example 9 Synthesis of[2-(1H-Benzotriazole-5-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-carbamicacid 3,5-dichloro-benzyl ester (48)

a. Synthesis of6-(3,5-Dichloro-benzyloxycarbonylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (46)

Starting material 45 (250 mg, 1.4 mmol) and 1,1′-carbonyl diimidazol(275 mg, 1.7 mmol) were dissolved in 2 ml DCM and stirred at roomtemperature for 3 h. Then starting material 44 (350 mg, 1.4 mmol) wasadded and the resulting mixture was stirred over night at roomtemperature. The reaction mixture was diluted with ethyl acetate, theorganic phase was washed with water 3 times, dried over Na₂SO₄, filteredand concentrated in vacuo. The remaining solid was purified over theprep. HPLC (Method 1), pure fractions were combined and concentrated invacuo yielding the desired product 46 as brown solid (170 mg, 0.377mmol, 27%).

b. Synthesis of (1,2,3,4-Tetrahydro-isoquinolin-6-yl)-carbamic acid3,5-dichloro-benzyl ester (47)

Starting material 46 (170 mg, 0.4 mmol) was dissolved in 5 ml propanol.Then 1 ml HCl in 2-propanol (5-6 N) was added and the mixture wasstirred over night at ambient temperature. The reaction mixture was thendiluted with diethyl ether, concentrated in vacuo and stirred withdiethyl ether, repeatedly decanting. Finally the solid residue wasfiltered off and dried in vacuo at 45° C. Thus the desired product 47was isolated as brownish crystals (46 mg, 0.1 mmol, 35%).

c. Synthesis of[2-(1H-Benzotriazole-5-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-carbamicacid 3,5-dichloro-benzyl ester (48)

Starting material 47 (46 mg, 0.1 mmol),1H-1,2,3-benzothiazole-5-carboxyllic acid (22 mg, 0.1 mmol) and 4-methylmorpholin (40 μL, 0.4 mmol) were dissolved in 2 ml DMF. Then EDCI (38mg, 0.2 mmol) and HOBt (26 mg, 0.2 mmol) were added and the mixture wasstirred over night at ambient temperature. The reaction mixture wasmixed with water and the resulting precipitate was filtered and dried invacuo at 45° C. The desired product 48 could thereby be isolated aslight brown solid (34 mg, 0.07 mmol, 52%).

Example 10 Synthesis of2-[2-(4-Chloro-2-fluoro-phenyl)-acetylamino]-6-(2-pyridin-3-yl-acetyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylicacid amide (50)

Starting material 49 (37 mg, 0.3 mmol) was dissolved in 2 ml dry DMF.Then EDCI (94 mg, 0.5 mmol) and HOBt (48 mg, 0.3 mmol) were addedyielding a yellow solution into which 100 mg of starting material 20(0.3 mmol) were added. Now the mixture was heated to 100° C. for 30minutes. The reaction mixture was cooled to ambient temperature, mixedwith water and the resulting precipitate was filtered and dried. Thiscrude product was further purified by prep HPLC (Method 4) yielding thedesired product 50 as light brown solid (53 mg, 0.1 mmol, 37%).

General Notes:

Analogously, p-chlorophenyl isocyanate was replaced by the followingisocyanates:

Analogously, (4-chloro-2-fluoro-phenyl)-acetic acid (18) was replaced bythe following acids:

Analogously, 1H-1,2,3-benzothiazole-5-carboxylic acid was replaced bythe following acids:

Analogously, Pyridin-3-yl-acetic acid (49) was replaced by the followingacids:

Analogously, pyridine-4-carbaldehyde (22) was replaced by the followingaldehydes:

Analogously, 6-amino-3H-benzooxazol-2-one (30) was replaced by thefollowing amines:

Analogously, 2-(4-Chloro-phenyl)-ethylamine (42) was replaced by thefollowing amines:

An overview about further analogously synthesized compounds of theinvention including physico-chemical parameters for all compounds of theinvention is given in Tables 2 and 3.

TABLE 2 ESI HPLC HPLC LC-MS Compound Chemical Name [M + 1]⁺ Rt [min]Method Method 1 6-(1H-Benzotriazole-5-carbonyl)-2- 496 2.93 A B[3-(4-chloro-phenyl)-ureido]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 22-[3-(4-Chloro-phenyl)-ureido]-6-(2- 512.1 2.95 A Boxo-2,3-dihydro-benzooxazole-6- (1.05) (G) (G)carbonyl)-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine-3-carboxylic acidamide 3 6-(1H-Benzotriazole-5-carbonyl)-2- 530.2 2.99 D B[3-(4-trifluoromethyl-phenyl)-ureido]- (1.08) (G) (G)4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide 46-(1H-Benzotriazole-5-carbonyl)-2- 504 3.03 A B[3-(4-isopropyl-phenyl)-ureido]- 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 5 6-(1H-Benzotriazole-5-carbonyl)-2-509 2.91 A B [3-(4-chloro-phenyl)- propionylamino]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 6 2-[3-(4-Chloro-phenyl)-525 3.03 A B propionylamino]-6-(2-oxo-2,3-dihydro-benzooxazole-6-carbonyl)- 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 72-[3-(4-Isopropyl-phenyl)-ureido]-6- 3.17 A B(2-oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 82-[3-(3,5-Dichloro-phenyl)-ureido]-6- 547 3.23 A B(2-oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 96-(1H-Benzotriazole-5-carbonyl)-2- 513 2.89 A B[2-(4-chloro-2-fluoro-phenyl)- acetylamino]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 102-[2-(4-Chloro-2-fluoro-phenyl)- 529 2.95 A Bacetylamino]-6-(2-oxo-2,3-dihydro- benzooxazole-6-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 116-(1H-Benzotriazole-5-carbonyl)-2- 495 2.81 A B[2-(3-chloro-phenyl)-acetylamino]- 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 12 6-(1H-Benzotriazole-5-carbonyl)-2-531 3.17 A B [3-(3,5-dichloro-phenyl)-ureido]-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide 132-[2-(3-Chloro-phenyl)-acetylamino]- 511 2.91 A B6-(2-oxo-2,3-dihydro-benzooxazole- 6-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 142-[2-(4-Chloro-phenyl)-acetylamino]- 511.1 2.92 A B6-(2-oxo-2,3-dihydro-benzooxazole- (1.01) (G) (G)6-carbonyl)-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine-3-carboxylic acidamide 15 6-(1H-Benzotriazole-5-carbonyl)-2- 514.1 2.87 A B[3-(4-chloro-2-fluoro-phenyl)-ureido]- (1.02) (G) (G)4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide 162-[2-(4-Chloro-2-fluoro-phenyl)- 459 2.5 A Bacetylamino]-6-pyridin-3-ylmethyl- 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 17 2-[2-(4-Chloro-2-fluoro-phenyl)-459 2.69 A B acetylamino]-6-pyridin-2-ylmethyl-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide 182-[3-(4-Chloro-phenyl)-ureido]-6- 442 2.73 A Bpyridin-2-ylmethyl-4,5,6,7- tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 19 2-[3-(4-Chloro-phenyl)-ureido]-6- 456 2.83 A B(pyridine-3-carbonyl)-4,5,6,7- tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 20 2-[3-(4-Chloro-phenyl)-ureido]-6- 442 2.57 A Bpyridin-4-ylmethyl-4,5,6,7- tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 21 2-[2-(4-Chloro-2-fluoro-phenyl)- 459 2.51 A Bacetylamino]-6-pyridin-4-ylmethyl- 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 22 2-[2-(4-Chloro-2-fluoro-phenyl)-487 2.63 A B acetylamino]-6-(2-pyridin-3-yl-acetyl)-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acidamide 23 2-[2-(4-Chloro-2-fluoro-phenyl)- 487 2.6 A Bacetylamino]-6-(2-pyridin-4-yl- acetyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 24 2-[2-(4-Chloro-2-fluoro-phenyl)-501 2.57 A B acetylamino]-6-(3-pyridin-2-yl-propionyl)-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine-3-carboxylic acidamide 25 6-(1H-Benzotriazole-5-carbonyl)-2- 510.9 3.29 A B[3-(4-chloro-phenyl)-ureido]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid methyl ester 262-[3-(4-Chloro-phenyl)-ureido]-6-(2- 526.9 3.35 A Boxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid methyl ester 271-[6-(1H-Benzotriazole-5-carbonyl)- 550 2.92 A B3-(pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]- 3-(4-chloro-phenyl)-urea 282-[3-(4-Chloro-phenyl)-ureido]-1H- 505 3.28 A C indole-3,6-dicarboxylicacid 3-amide 6-[(2-oxo-2,3-dihydro-benzooxazol- 6-yl)-amide] 292-[2-(4-Chloro-2-fluoro-phenyl)- 497 3.13 A Cacetylamino]-benzothiazole-6- carboxylic acid (2-oxo-2,3-dihydro-benzooxazol-6-yl)-amide 30 2-[3-(4-Trifluoromethyl-phenyl)- 480 3.23 A Cureido]-benzothiazole-6-carboxylic acid (2-oxo-2,3-dihydro-benzooxazol-6-yl)-amide 31 2-[3-(4-Chloro-phenyl)-ureido]- 480 3.13 A Cbenzothiazole-6-carboxylic acid (2- oxo-2,3-dihydro-benzooxazol-6-yl)-amide 32 2-[3-(4-Trifluoromethyl-phenyl)- 498 3.2 A Cureido]-benzothiazole-6-carboxylic acid (1H-benzotriazol-5-yl)-amide 336-(1H-Benzotriazole-5-carbonyl)- 470 not F E4,5,6,7-tetrahydro-2H-pyrazolo[3,4- available c]pyridine-3-carboxylicacid 3,5- dichloro-benzylamide 34 6-(1H-Benzotriazole-5-carbonyl)- 436.2not F E 4,5,6,7-tetrahydro-2H-pyrazolo[3,4- availablec]pyridine-3-carboxylic acid 4-chloro- benzylamide 356-(1H-Benzotriazole-5-carbonyl)- 464.2 3.65 F E4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylic acid [2-(4-chloro-phenyl)-propyl]-amide 36 6-(1H-Benzotriazole-5-carbonyl)- 488.23.6 F E 4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylic acid2-fluoro- 5-trifluoromethyl-benzylamide 376-(1H-Benzotriazole-5-carbonyl)- 484 4.5 F E4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylic acid[2-(3,4- dichloro-phenyl)-ethyl]-amide 386-(1H-Benzotriazole-5-carbonyl)- 470 3.52 F E4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylic acid 2,5-dichloro-benzylamide 39 6-(1H-Benzotriazole-5-carbonyl)- 450.2 4.32 F E4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide 40 6-(1H-Benzotriazole-5-carbonyl)- 480.23.01 F E 4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylicacid [2-(4- chloro-phenyl)-1-hydroxymethyl- ethyl]-amide 416-(1H-Benzotriazole-5-carbonyl)- 432.2 2.99 F E4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylic acid 2-methoxy-benzylamide 42 6-(1H-Benzotriazole-5-carbonyl)- 450.2 3.39 F E4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide 43 6-(1H-Benzotriazole-5-carbonyl)- 461.13.12 F E 4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylicacid [2-(4- nitro-phenyl)-ethyl]-amide 446-(1H-Benzotriazole-5-carbonyl)- 496.1 3.52 F E4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylic acid [2-(4-bromo-phenyl)-ethyl]-amide 45 6-(1H-Benzotriazole-5-carbonyl)- 466.13.41 F E 4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylicacid 5-chloro- 2-methoxy-benzylamide 46 6-(1H-Benzotriazole-5-carbonyl)-454.1 3.39 F E 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylic acid 4-chloro- 2-fluoro-benzylamide 476-(1H-Benzotriazole-5-carbonyl)- 434.2 3.23 F E4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide 48 [2-(1H-Benzotriazole-5-carbonyl)- 4964.61 F E 1,2,3,4-tetrahydro-isoquinolin-6-yl]- carbamic acid3,5-dichloro-benzyl ester

TABLE 3 HPLC HPLC ESI Rt [min] Rt [min] Compound Chemical Name [M + 1]⁺Method F Method E 49 6-(1H-Benzotriazole-5-carbonyl)- 502 3.82 2.104,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylic acid 4-trifluoromethylsulfanyl-benzylamide 503-(1H-Benzotriazol-5-ylcarbamoyl)- 486 4.08 2.281,4,5,7-tetrahydro-pyrazolo[3,4- c]pyridine-6-carboxylic acid 4-trifluoromethyl-benzyl ester 51 6-(1H-Benzotriazole-5-carbonyl)- 498,500 3.47 1.91 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylic acid 3-bromo- 4-fluoro-benzylamide 523-(1H-Benzotriazol-5-ylcarbamoyl)- 487 4.07 2.222,4,5,7-tetrahydro-pyrazolo[3,4- c]pyridine-6-carboxylic acid 3,5-dichloro-benzyl ester 53 3-(1H-Benzotriazol-5-ylcarbamoyl)- 554 4.232.36 2,4,5,7-tetrahydro-pyrazolo[3,4- c]pyridine-6-carboxylic acid3,5-bis- trifluoromethyl-benzyl ester 543-(1H-Benzotriazol-5-ylcarbamoyl)- 521 4.29 2.242,4,5,7-tetrahydro-pyrazolo[3,4- c]pyridine-6-carboxylic acid 3-chloro-4-trifluoromethyl-benzyl ester 55 3-(1H-Benzotriazol-5-ylcarbamoyl)- 4864.03 2.21 2,4,5,7-tetrahydro-pyrazolo[3,4- c]pyridine-6-carboxylic acid3- trifluoromethyl-benzyl ester 56 3-(1H-Benzotriazol-5-ylcarbamoyl)-518 4.35 2.27 2,4,5,7-tetrahydro-pyrazolo[3,4- c]pyridine-6-carboxylicacid 4- trifluoromethylsulfanyl-benzyl ester 573-(1H-Benzotriazol-5-ylcarbamoyl)- 502 4.16 2.282,4,5,7-tetrahydro-pyrazolo[3,4- c]pyridine-6-carboxylic acid 4-trifluoromethoxy-benzyl ester 58 3-(1H-Benzotriazol-5-ylcarbamoyl)- 5374.37 2.29 2,4,5,7-tetrahydro-pyrazolo[3,4- c]pyridine-6-carboxylic acid3-chloro- 4-trifluoromethoxy-benzyl ester 59(1H-Benzotriazol-5-yl)-{3-[3-(4- 487 3.39 1.83methoxy-phenyl)-piperidine-1- carbonyl]-2,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl}- methanone 606-(1H-Benzotriazole-5-carbonyl)- 486 3.60 2.044,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylic acid 4-trifluoromethoxy-benzylamide 61 6-(1H-Benzotriazole-5-carbonyl)- 4703.52 2.01 4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridine-3-carboxylicacid 4- trifluoromethyl-benzylamide 62 6-(1H-Benzotriazole-5-carbonyl)-473 3.41 1.84 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (6- methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amide 63 3-{[6-(1H-Benzotriazole-5-carbonyl)- 531 4.002.19 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carbonyl]-amino}-3-(4- tert-butyl-phenyl)-propionic acidmethyl ester

In the following ¹H-NMR data for selected compounds of the invention aredisplayed:

Compound 33, C₂₁H₁₇Cl₂N₇O₂

¹H NMR (500 MHz, DMSO-d6) δ [ppm]=13.15 (s, 1H), 8.75 (s, 1H), 8.03 (s,1H), 7.99 (d, J=8.4, 1H), 7.50 (d, J=8.4, 1H), 7.47 (s, 1H), 7.34 (s,2H), 4.79 (s, 2H), 4.40 (s, 2H), 4.12-3.65 (m, 2H), 2.95-2.60 (m, 3H).

Compound 37, C₂₂H₁₉Cl₂N₇O₂

¹H NMR (500 MHz, DMSO-d6) δ [ppm]=16.08 (s, 1H), 13.22-12.55 (m, 1H),8.18-7.92 (m, 3H), 7.60-7.52 (m, 3H), 7.22 (d, J=8.0, 1 H), 4.90-4.45(m, 2H), 3.85 (s, 1H), 3.60-3.40 (m, 3H), 2.84 (t, J=12.3, 2H), 2.76 (s,2H).

Compound 48, C₂₄H₁₉Cl₂N₅O₃

¹H NMR (500 MHz, DMSO-d6) δ [ppm]=9.76 (s, 1H), 8.05-7.87 (m, 2H), 7.58(s, 1H), 7.49 (s, 3H), 7.35-7.12 (m, 3H), 5.15 (s, 2H), 4.82-4.40 (m,2H), 4.02-3.50 (m, 2H), 2.84 (s, 2H), 2.35-2.20 (m, 1H).

Compound 19, C₂₁H₁₈ClN₅O₃S

¹H NMR (500 MHz, DMSO) δ [ppm]=10.86 (s, 1H), 10.20 (s, 1H), 8.71 (d,J=4.5, 2H), 7.91 (s, 1H), 7.52 (m, 3H), 7.35 (d, J=8.1, 2H), 7.6-7.2(br. s, 1H), 6.98 (br. s, 1H), 4.74 (s, 0.67×2H) and 4.56 (s, 0.33×2H),3.90 (s, 0.33×2H) and 3.55 (s, 0.67×2H), 2.91 (s, 2H).

Compound 7, C₂₆H₂₅N₅O₅S

¹H NMR (500 MHz, DMSO) δ [ppm]=11.86 (s, 1H), 10.76 (s, 1H), 9.95 (s,1H), 7.41 (s, 1H), 7.39 (d, J=8.3, 2H), 7.29 (d, J=7.9, 1 H), 7.17 (m,3H), 7.6-7.1 (br. s, 1H), 7.00 (br. s, 1H), 4.65 (s, 2H), 3.54 (m, 2H),3.06-2.69 (m, 3H), 1.19 (d, J=6.9, 6H).

Compound 29, C₂₃H₁₄ClFN₄O₄S

¹H NMR (400 MHz, DMSO) δ [ppm]=12.83 (s, 1H), 11.54 (s, 1H), 10.33 (s,1H), 8.59 (d, J=1.7, 1H), 8.03 (dd, J=8.5, 1.7, 1H), 7.86 (t, J=8.5,1H), 7.83 (d, J=1.7, 1H), 7.54-7.41 (m, 3H), 7.30 (dd, J=8.2, 1.9, 1H),7.08 (d, J=8.4, 1H), 3.97 (s, 2H).

Compound 31, C₂₂H₁₄ClN₅O₄S

¹H NMR (400 MHz, DMSO) δ [ppm]=11.58 (s, 1H), 10.33 (s, 1H), 9.36 (s,1H), 8.53 (s, 1H), 8.03-7.94 (m, 1H), 7.84 (d, J=1.9, 1H), 7.80-7.66 (m,2H), 7.59 (m, 2H), 7.51 (dd, J=8.5, 1.9, 1H), 7.44-7.36 (m, 2H), 7.09(d, J=8.4, 1H).

2-Amino-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acidmethyl ester hydrochloride (17), C₉H₁₂N₂O₂S*HCl

¹H NMR (400 MHz, DMSO) δ [ppm]=7.35 (s, 2H), 4.59 (s, 2H), 3.77 (s, 2H),3.68 (s, 3H), 3.04 (t, J=5.9, 2H), 2.73-2.66 (m, 2H).

Compound 50

¹H NMR (500 MHz, DMSO) δ=15.53 (s, 1H), 13.22 (s, 1H), 10.25 (s, 1H),8.47 (s, 1H), 7.89 (s, 1H), 7.83-7.68 (m, 3H), 7.63 (d, J=8.0, 2H), 5.25(s, 2H), 4.72-4.58 (m, 2H), 3.72 (s, 2H), 2.85 (s, 2H).

Compound 51

¹H NMR (500 MHz, DMSO) δ=15.87 (s, 1H), 13.10 (s, 1H), 8.69 (s, 1H),8.07-7.90 (m, 2H), 7.61 (s, 1H), 7.49 (d, J=8.5, 1 H), 7.40-7.24 (m,2H), 4.77 (s, 2H), 4.38 (s, 2H), 3.81 (s, 1H), 3.53 (s, 1H), 2.79 (s,2H).

Compound 52

¹H NMR (500 MHz, DMSO, d-TFA exchanged, C₂₁H₁₄D₃Cl₂N₇O₃) δ=8.48 (d,J=1.6, 1H), 7.82 (d, J=9.0, 1H), 7.68 (dd, J=9.0, 1.6, 1H), 7.35-7.27(m, 3H), 5.06 (s, 2H), 4.65-4.53 (m, 2H), 3.64 (s, 2H), 2.82 (t, J=5.3,2H).

Compound 53

¹H NMR (500 MHz, DMSO) δ=15.54 (s, 1H), 13.22 (s, 1H), 10.24 (s, 1H),8.46 (s, 1H), 8.13-8.07 (m, 3H), 7.89 (d, J=7.9, 1H), 7.75 (s, 1H), 5.32(s, 2H), 4.72-4.57 (m, 2H), 3.71 (s, 2H), 2.84 (s, 2H).

Compound 54

¹H NMR (500 MHz, DMSO) δ=15.50 (s, OH, 1H), 13.22 (s, 1H), 10.24 (s,1H), 8.46 (s, 1H), 7.89 (d, J=8.2, 2H), 7.79-7.70 (m, 2H), 7.58 (d,J=8.2, 1H), 5.24 (s, 2H), 4.75-4.60 (m, 2H), 3.79-3.63 (m, 2H), 2.86 (s,2H).

Compound 55

¹H NMR (500 MHz, DMSO) δ=15.50 (s, 1H), 13.20 (s, 1H), 10.22 (s, 1H),8.45 (s, 1H), 7.88 (d, J=7.9, 1H), 7.78-7.66 (m, 4H), 7.63 (t, J=7.7,1H), 5.23 (s, 2H), 4.62 (s, 2H), 3.69 (s, 2H), 2.83 (t, J=5.4, 2H).

Compound 58

¹H NMR (500 MHz, DMSO) δ=15.54 (s, 1H), 13.22 (s, 1H), 10.25 (s, 1H),8.47 (s, 1H), 7.89 (s, 1H), 7.80-7.73 (m, 2H), 7.60 (d, J=8.7, 1H), 7.52(dd, J=8.5, 1.9, 1H), 5.18 (s, 2H), 4.70-4-58 (m, 2H), 3.70 (s, 2H),2.85 (s, 2H).

Compound 60

¹H NMR (500 MHz, DMSO) δ=15.75 (s, 1H), 13.09 (s, 1H), 8.65 (s, 1H),8.07-7.92 (m, 2H), 7.49 (d, J=8.5, 1H), 7.42 (d, J=8.4, 2H), 7.30 (d,J=8.2, 2H), 4.88-4.55 (m, 2H), 4.42 (d, J=5.2, 2H), 3.99-3.45 (m, 2H),2.80 (s, 2H).

The following analytical methods were use for determining aboveillustrated physico-chemical parameters:

ESI: Electrospray Ionization Mass Spectrometry (M+H)+

Analytical Chromatography Methods

A HPLC-Method: 1_(—)100_(—)2 Speed (machine: LaChrom)

Column: Chromolith Performance RP18e 100-3 mm

Flow: 2 ml/min (Pump: L-7100)

Solvent A: water+0.01% TFA

Solvent B: Acetonitrile+0.01% TFA

Wavelength (WL): 220 nm (Detector: L-7455)

0-0.2 100% A, 0.2-3.7 to 100% B, 3.7-4.4 100% B, 4.5-5.0 100% A

B LC-MS-Method: polar.M (machine: Agilent 1100 Series)

Column: Chromolith Speed Rod RP18e-50-4.6

Flow: 2.4 m l/m in

Solvent A: water+0.1% TFA

Solvent B: Acetonitrile+0.1% TFA

WL: 220 nm

Gradient: 0-2.6 min: 4% B to 100% B, 2.6-3.3 min: 100% B

C LC-MS-Method: polar.M (machine: Agilent 1100 Series)

Column: Chromolith Speed Rod RP18e-50-4.6

Flow: 2.4 ml/m in

Solvent A: water+0.05% HCOOH

Solvent B: Acetonitrile+0.04% HCOOH

WL: 220 nm

Gradient: 0-2.8 min: 4% B to 100% B, 2.8-3.3 min: 100% B

D HPLC-Method: 1_(—)100_(—)2 (machine: LaChrom)

Column: Chromolith Performance RP18e 100-3 mm

Flow: 2 ml/min (Pump: L-7100)

Solvent A: water+0.01% HCOOH

Solvent B: Acetonitrile+0.01% HCOOH

WL: 220 nm (Detector: L-7455)

0-0.2 100% A, 0.2-3.7 to 100% B, 3.7-4.4 100% B, 4.5-5.0 100% A

E HPLC/MS-Method (polar)

Solvent A: water+0.05% HCOOH

Solvent B: Acetonitrile+0.04% HCOOH

Flow: 2.4 ml/min, WL: 220 nm

Gradient: 0.0 min 4% B

-   -   2.8 min 100% B    -   3.3 min 100% B    -   3.4 min 4% B

Column: Chromolith® Speed ROD RP-18e 50-4.6 mm

F HPLC-Method (non-polar)

-   -   Solvent A: water+0.1% TFA    -   Solvent B: Acetonitrile+0.08% TFA    -   Flow: 1.5 ml/min    -   Gradient: 0.0 min 20% B

5.0 min 100% B

5.5 min 100% B

6.0 min 20% B

6.5 min 20% B

Column: Chromolith Performance RP18e 100-3

G HPLC/MS-Method

Machine: Waters Acquity HPLC® with PDA and ELSD; Waters SQD (ESI+/− andAPCI+/−)

Solvent A: Acetonitrile+0.1% HCOOH

Solvent B: Water+0.1% HCOOH

Flow: 1 ml/min, WL: 254 nm

Gradient: 0.0 min 1% A

-   -   1.7 min 99% A    -   2.0 min 99% A

Column: Acquity HPLC® BEH C18 (2.1×50 mm)

Column Temperature: 60° C.

Preparative Chromatography Methods:

Prep.-HPLC-Method 1:

Machine: Agilent 1100 Series

Column: Chromolith Prep Rod RP18e

flow: 50 ml/min

Solvent A: Acetonitrile+0.1% TFA

Solvent B: water+0.1% TFA

WL: 220 nm

Gradient: from 1-20% ACN in 2 min, from 20-40% ACN in 8 min, collectfrom 2 min to 11 min

Prep.-HPLC-Method 2:

Machine: Agilent 1100 Series

Column: Chromolith Prep Rod RP18e

Flow: 50 ml/min

Solvent A: Acetonitrile+0.1% TFA

Solvent B: Water+0.1% TFA

WL: 220 nm

Gradient: from 1-30% ACN in 10 min, collect from 2 min to 11 min

Prep.-HPLC-Method 3:

machine: Agilent 1100 Series

Column: Chromolith Prep Rod RP18e

flow: 50 ml/min

Solvent A: Acetonitrile+0.1% TFA

Solvent B: Water+0.1% TFA

WL: 220 nm

Gradient: from 1-25% ACN in 2 min, from 25-50% ACN in 8 min, collectfrom 2 min to 11 min

Prep.-HPLC-Method 4:

Machine: Agilent 1100 Series

Column: Chromolith Prep Rod RP18e

flow: 50 ml/min

Solvent A: Acetonitrile+0.1% TFA

Solvent B: Water+0.1% TFA

WL: 220 nm

Gradient: from 1-15% ACN in 2 min, from 15-35% ACN in 8 min, collectfrom 2 min to 11 min

Flashmaster Method 1:

Machine: Flashmaster

Column material: Chromolith NH₂

solvent: ethyl acetate (EE)/MeOH

Gradient: 100% EE 5 min, in 15 min to 3% MeOH, in 16 min to 4% MeOH, in15 min to 10% MeOH, 15 min MeOH flush

II. Autotaxin Assay Assay Description

Autotaxin activity is measured indirectly by means of Amplex RedReagent. In this course, Amplex Red is measured as fluorogenic indicatorfor generated H₂O₂. Autotaxin converts substrate lysophosphatidylcholine(LPC) to phosphocholine and lysophosphatidylic acid (LPA). After theconversion phosphocholine is reacted with alkaline phosphatase to obtaininorganic phosphate and choline. During the next step choline isoxidized with choline oxidase to yield betaine, whereby H₂O₂ isgenerated. H₂O₂ reacts with Amplex Red Reagent in the presence ofperoxidase (Horseradish peroxidase) in an 1:1 stochiometry and yieldshighly fluorescent resorufin. The generated fluorescence is measured ina reaction-dependent kinetic mode in order to enable subtraction offluorescence signals of possible other fluorescent compounds that arenot part of the reaction from total measured fluorescence.

Performing the Assay

1.5 μl of a standard solution or of the compounds of the invention aredissolved in 20 mM Hepes pH 7.2 with maximally 7.7% DMSO in individualconcentrations. The resulting solution is pre-incubated together with 10μl (16 ng) of highly purified recombinant autotaxin in a black 384-holemicrotiter plate for 30 min at 22° C.

Thereafter, the reaction is started through the addition of 5μL-a-lysophosphatidyl-choline (LPC), whereby the final concentration ofLPC is 75 μM. The mixture is incubated for 90 min. at 37° C. After theincubation Amplex Red Reagent, peroxidase (Horseradish peroxidase) andcholine oxidase are added. The fluorescence is immediately measured at awavelength of 612 nm with an excitation wavelength of 485 nm in a “TecanUltra multimode” fluorescence reader. The activity of autotaxin isindirectly calculated via the amount of detected generated H₂O₂.

For IC₅₀ analysis, ten serial 1:3 dilutions starting at 30 μM for eachcompound were run in duplicates.

IC₅₀ values were calculated on normalized data. For normalization,control wells were added to each assay plate and the signal ofuninhibited control wells was set to 100%, whereas the signal inhibitedby 500 μM C14 LPA, (Avanti Polar Lipids, Cat#857120P) was set to 0%.Curves were fitted and IC₅₀ values calculated by the following modelusing proprietary analysis software:

Y=Bottom+(100−Bottom)/(1+10̂((Log IC₅₀ −X)*HillSlope))

Where X is the logarithm of concentration. Y is the response; Y startsat Bottom and goes to Top with a sigmoid shape.

Material

Microtiter plate: PS-Microplate, 384-hole, small volume, black Corning,Cat#3677Protein: Recombinant autotaxin (baculoviral Hi5 expression)Substrate: L-a-lysophosphatidyl choline (chicken egg); Avanti PolarLipids #830071P

Standard: C14 LPA, Avanti Polar Lipids, Cat# 857120P

Detection Reagent: Amplex Red Reagent; Invitrogen #A12222; dissolved in1.923 ml of DMSO peroxidase Type VI-A (horseradish), Sigma #P6782;dissolved in 7.45 ml of test buffer, Choline Oxidase; Sigma #C5896;dissolved in 2.47 ml test bufferDetection Reagent Mix: 1:100 dilution of Amplex Red Regent in testbufferTest buffer: 200 mM Tris-HCl, Merck, Cat #1.08219, pH 7.9; 0.1% BSA,lipid free, Roche Cat#775835

TABLE 4 Com- IC₅₀ value [M] or pound Chemical Name % CTRL (1E−05) 16-(1H-Benzotriazole-5-carbonyl)-2-[3-(4- <1.00E−06chloro-phenyl)-ureido]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 22-[3-(4-Chloro-phenyl)-ureido]-6-(2-oxo- <1.00E−062,3-dihydro-benzooxazole-6-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 36-(1H-Benzotriazole-5-carbonyl)-2-[3-(4- <1.00E−06trifluoromethyl-phenyl)-ureido]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 46-(1H-Benzotriazole-5-carbonyl)-2-[3-(4- <1.00E−06isopropyl-phenyl)-ureido]-4,5,6,7- tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 5 6-(1H-Benzotriazole-5-carbonyl)-2-[3-(4-<1.00E−06 chloro-phenyl)-propionylamino]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 62-[3-(4-Chloro-phenyl)-propionylamino]-6- <1.00E−06(2-oxo-2,3-dihydro-benzooxazole-6-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acidamide 7 2-[3-(4-Isopropyl-phenyl)-ureido]-6-(2-oxo- <1.00E−062,3-dihydro-benzooxazole-6-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 82-[3-(3,5-Dichloro-phenyl)-ureido]-6-(2- <1.00E−05oxo-2,3-dihydro-benzooxazole-6-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 96-(1H-Benzotriazole-5-carbonyl)-2-[2-(4- <1.00E−06chloro-2-fluoro-phenyl)-acetylamino]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 102-[2-(4-Chloro-2-fluoro-phenyl)- <1.00E−06acetylamino]-6-(2-oxo-2,3-dihydro- benzooxazole-6-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 116-(1H-Benzotriazole-5-carbonyl)-2-[2-(3- <1.00E−06chloro-phenyl)-acetylamino]-4,5,6,7- tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 12 6-(1H-Benzotriazole-5-carbonyl)-2-[3-(3,5-<1.00E−05 dichloro-phenyl)-ureido]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid amide 132-[2-(3-Chloro-phenyl)-acetylamino]-6-(2- <1.00E−06oxo-2,3-dihydro-benzooxazole-6-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 142-[2-(4-Chloro-phenyl)-acetylamino]-6-(2- <1.00E−06oxo-2,3-dihydro-benzooxazole-6-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 156-(1H-Benzotriazole-5-carbonyl)-2-[3-(4- <1.00E−06chloro-2-fluoro-phenyl)-ureido]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 162-[2-(4-Chloro-2-fluoro-phenyl)- <3.00E−05acetylamino]-6-pyridin-3-ylmethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 172-[2-(4-Chloro-2-fluoro-phenyl)- 66%acetylamino]-6-pyridin-2-ylmethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 182-[3-(4-Chloro-phenyl)-ureido]-6-pyridin-2- 88%ylmethyl-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acidamide 19 2-[3-(4-Chloro-phenyl)-ureido]-6-(pyridine- <1.00E−053-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acidamide 20 2-[3-(4-Chloro-phenyl)-ureido]-6-pyridin-4- <1.00E−05ylmethyl-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acidamide 21 2-[2-(4-Chloro-2-fluoro-phenyl)- <1.00E−05acetylamino]-6-pyridin-4-ylmethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 222-[2-(4-Chloro-2-fluoro-phenyl)- <1.00E−05acetylamino]-6-(2-pyridin-3-yl-acetyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 232-[2-(4-Chloro-2-fluoro-phenyl)- <1.00E−05acetylamino]-6-(2-pyridin-4-yl-acetyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 242-[2-(4-Chloro-2-fluoro-phenyl)- <1.00E−05acetylamino]-6-(3-pyridin-2-yl-propionyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid amide 256-(1H-Benzotriazole-5-carbonyl)-2-[3-(4- <3.00E−05chloro-phenyl)-ureido]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid methyl ester 262-[3-(4-Chloro-phenyl)-ureido]-6-(2-oxo- <1.00E−052,3-dihydro-benzooxazole-6-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3- carboxylic acid methyl ester27 1-[6-(1H-Benzotriazole-5-carbonyl)-3- 52%(pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-(4-chloro- phenyl)-urea 282-[3-(4-Chloro-phenyl)-ureido]-1H-indole- <3.00E−05 3,6-dicarboxylicacid 3-amide 6-[(2-oxo- 2,3-dihydro-benzooxazol-6-yl)-amide] 292-[2-(4-Chloro-2-fluoro-phenyl)- <1.00E−05acetylamino]-benzothiazole-6-carboxylic acid(2-oxo-2,3-dihydro-benzooxazol-6-yl)- amide 302-[3-(4-Trifluoromethyl-phenyl)-ureido]- 93% benzothiazole-6-carboxylicacid (2-oxo-2,3- dihydro-benzooxazol-6-yl)-amide 312-[3-(4-Chloro-phenyl)-ureido]- 94% benzothiazole-6-carboxylic acid(2-oxo-2,3- dihydro-benzooxazol-6-yl)-amide 322-[3-(4-Trifluoromethyl-phenyl)-ureido]- 64% benzothiazole-6-carboxylicacid (1H- benzotriazol-5-yl)-amide 336-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <1.00E−05tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid3,5-dichloro-benzylamide 34 6-(1H-Benzotriazole-5-carbonyl)-4,5,6,7-<1.00E−05 tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid4-chloro-benzylamide 35 6-(1H-Benzotriazole-5-carbonyl)-4,5,6,7-<1.00E−05 tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid[2-(4-chloro-phenyl)- propyl]-amide 366-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <3.00E−05tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid2-fluoro-5-trifluoromethyl- benzylamide 376-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <1.00E−05tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid[2-(3,4-dichloro-phenyl)- ethyl]-amide 386-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <1.00E−05tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid2,5-dichloro-benzylamide 39 6-(1H-Benzotriazole-5-carbonyl)-4,5,6,7-<1.00E−06 tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid[2-(4-chloro-phenyl)-ethyl]- amide 406-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- 73%tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid[2-(4-chloro-phenyl)-1- hydroxymethyl-ethyl]-amide 416-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- 66%tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid2-methoxy-benzylamide 42 6-(1H-Benzotriazole-5-carbonyl)-4,5,6,7-<3.00E−05 tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid[2-(3-chloro-phenyl)-ethyl]- amide 436-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <1.00E−05tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid[2-(4-nitro-phenyl)-ethyl]- amide 446-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <1.00E−05tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid[2-(4-bromo-phenyl)-ethyl]- amide 456-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <1.00E−05tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid5-chloro-2-methoxy- benzylamide 466-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- 76%tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid4-chloro-2-fluoro- benzylamide 476-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <1.00E−05tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid[2-(4-fluoro-phenyl)-ethyl]- amide 48[2-(1H-Benzotriazole-5-carbonyl)-1,2,3,4- <1.00E−05tetrahydro-isoquinolin-6-yl]-carbamic acid 3,5-dichloro-benzyl ester 496-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <3.00E−05tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid4-trifluoromethylsulfanyl- benzylamide 503-(1H-Benzotriazol-5-ylcarbamoyl)-1,4,5,7- <1.00E−06tetrahydro-pyrazolo[3,4-c]pyridine-6- carboxylic acid4-trifluoromethyl-benzyl ester 516-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <1.00E−06tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid3-bromo-4-fluoro- benzylamide 523-(1H-Benzotriazol-5-ylcarbamoyl)-2,4,5,7- <1.00E−06tetrahydro-pyrazolo[3,4-c]pyridine-6- carboxylic acid3,5-dichloro-benzyl ester 53 3-(1H-Benzotriazol-5-ylcarbamoyl)-2,4,5,7-<1.00E−06 tetrahydro-pyrazolo[3,4-c]pyridine-6- carboxylic acid3,5-bis-trifluoromethyl- benzyl ester 543-(1H-Benzotriazol-5-ylcarbamoyl)-2,4,5,7- <1.00E−05tetrahydro-pyrazolo[3,4-c]pyridine-6- carboxylic acid3-chloro-4-trifluoromethyl- benzyl ester 553-(1H-Benzotriazol-5-ylcarbamoyl)-2,4,5,7- <1.00E−06tetrahydro-pyrazolo[3,4-c]pyridine-6- carboxylic acid3-trifluoromethyl-benzyl ester 563-(1H-Benzotriazol-5-ylcarbamoyl)-2,4,5,7- <1.00E−06tetrahydro-pyrazolo[3,4-c]pyridine-6- carboxylic acid4-trifluoromethylsulfanyl- benzyl ester 573-(1H-Benzotriazol-5-ylcarbamoyl)-2,4,5,7- <1.00E−05tetrahydro-pyrazolo[3,4-c]pyridine-6- carboxylic acid4-trifluoromethoxy-benzyl ester 583-(1H-Benzotriazol-5-ylcarbamoyl)-2,4,5,7- <1.00E−06tetrahydro-pyrazolo[3,4-c]pyridine-6- carboxylic acid3-chloro-4-trifluoromethoxy- benzyl ester 59(1H-Benzotriazol-5-yl)-{3-[3-(4-methoxy- <3.00E−05phenyl)-piperidine-1-carbonyl]-2,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl}- methanone 606-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <3.00E−05tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid4-trifluoromethoxy- benzylamide 616-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <1.00E−05tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid4-trifluoromethyl- benzylamide 626-(1H-Benzotriazole-5-carbonyl)-4,5,6,7- <1.00E−05tetrahydro-2H-pyrazolo[3,4-c]pyridine-3- carboxylic acid(6-methoxy-1,2,3,4- tetrahydro-naphthalen-2-yl)-amide 633-{[6-(1H-Benzotriazole-5-carbonyl)- <3.00E−054,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carbonyl]-amino}-3-(4-tert- butyl-phenyl)-propionic acidmethyl ester

1. Compound according to formula (I)

wherein: W₁, W₂ together independently form “—N═N—, —C(O)—O—, —C(O)—S—,—C(O)—N(R5)-, —C(O)—C(R6)(R7)-, —N═C[N(R8)(R9)]-”; Y₁ is independentlyselected from the group consisting of “—C(O)—, —C(S)—, —N(R10)-C(O)—,—C(O)—N(R11)-, —C(R12)(R13)-, single bond”; Y₂ is independently selectedfrom the group consisting of “—C(R14)(R15)-, —O—, —N(R16)-, —C(O)—NH—,single bond”; Z₁ is independently selected from the group consisting of“O, S, N(R17)”; L is independently selected from the group consisting ofthe group consisting of:

B is independently selected from the group consisting of “cycloalkyl,heterocyclyl, aryl, heteroaryl”, wherein “cycloalkyl, heterocyclyl,aryl, heteroaryl” can be independently substituted with one or moreidentical or different substituents selected from the group consistingof: “(i) “hydrogen, alkyl, (C₉-C₃₀)alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halogen, —F, —Cl, —Br, —I, —CN, —CF₃, —N₃, —NH₂, —NHX1,—NX2X3, —NO₂, —OH, —OCF₃, —SCF₃, —SH, —O—SO₃H, —OP(O)(OH)₂, —CHO, —COOH,—C(O)NH₂, —SO₃H, —P(O)(OH)₂, —C(O)—X4, —C(O)O—X5, —C(O)NH—X6,—C(O)NX7X8, —O—X9, —O(—X10-O)_(a)—H (a=1, 2, 3, 4, 5),—O(—X11-O)_(b)—X12 (b=1, 2, 3, 4, 5), —OC(O)—X13, —OC(O)—O—X14,—OC(O)—NHX15, —O—C(O)—NX16X17, —OP(O)(OX18)(OX19), —OSi(X20)(X21)(X22),—OS(O₂)—X23, —NHC(O)—NH₂, —NHC(O)—X24, —NX25C(O)—X26, —NH—C(O)—O—X27,—NH—C(O)—NH—X28, —NH—C(O)—NX29X30, —NX31-C(O)—O—X32, —NX33-C(O)—NH—X34,—NX35-C(O)—NX36X37, —NHS(O₂)—X38, —NX39S(O₂)—X40, —S—X41, —S(O)—X42,—S(O₂)—X43, —S(O₂)NH—X44, —S(O₂)NX45X46, —S(O₂)O—X47, —P(O)(OX48)(OX49),—Si(X50)(X51)(X52), —C(NH)—NH₂, —C(NX53)-NH₂, —C(NH)—NHX54,—C(NH)—NX55X56, —C(NX57)-NHX58, —C(NX59)-NX60X61, —NH—C(O)—NH—O—X62,—NH—C(O)—NX63-O—X64, —NX65-C(O)—NX66-O—X67, —N(—C(O)—NH—O—X68)₂,—N(—C(O)—NX69-O—X70)₂, —N(—C(O)—NH—O—X71)(—C(O)—NX72-O—X73), —C(S)—X74,—C(S)—O—X75, —C(S)—NH—X76, —C(S)—NX77X78, —C(O)—NH—O—X79,—C(O)—NX80-O—X81, —C(S)—NH—O—X82, —C(S)—NX83-O—X84, —C(O)—NH—NH—X85,—C(O)—NH—NX86X87, —C(O)—NX88-NX89X90, —C(S)—NH—NH—X91, —C(S)—NH—NX92X93,—C(S)—NX94-NX95X96, —C(O)—C(O)—O—X97, —C(O)—C(O)—NH₂, —C(O)—C(O)—NHX98,—C(O)—C(O)—NX99X100, —C(S)—C(O)—O—X101, —C(O)—C(S)—O—X102,—C(S)—C(S)—O—X103, —C(S)—C(O)—NH₂, —C(S)—C(O)—NHX104,—C(S)—C(O)—NX105X106, —C(S)—C(S)—NH₂, —C(S)—C(S)—NHX107,—C(S)—C(S)—NX108X109, —C(O)—C(S)—NH₂, —C(O)—C(S)—NHX110,—C(O)—C(S)—NX111X112”; wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10,X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24,X25, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38,X39, X40, X41, X42, X43, X44, X45, X46, X47, X48, X49, X50, X51, X52,X53, X54, X55, X56, X57, X58, X59, X60, X61, X62, X63, X64, X65, X66,X67, X68, X69, X70, X71, X72, X73, X74, X75, X76, X77, X78, X79, X80,X81, X82, X83, X84, X85, X86, X87, X88, X89, X90, X91, X92, X93, X94,X95, X96, X97, X98, X99, X100, X101, X102, X103, X104, X105, X106, X107,X108, X109, X110, X111, X112 are independently from each other selectedfrom the group consisting of: “alkyl, (C₉-C₃₀)alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl” and wherein alternatively X7, X8 and/orX16, X17 and/or X29, X30 and/or X36, X37 and/or X45, X46 and/or X55, X56and/or X60, X61 and/or X77, X78 and/or X86, X87 and/or X89, X90 and/orX92, X93 and/or X95, X96 and/or X99, X100 and/or X105, X106 and/or X108,X109 and/or X111, X112 respectively together can also form“heterocyclyl”; wherein optionally above substituents of substituentsgroup (i) can in turn independently from each other be substituted withone or more identical or different substituents V; R1, R2, R3, R4, R5,R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17 are independentlyfrom each other selected from the group consisting of: “V”; V isindependently selected from the group consisting of: “(i) “hydrogen,alkyl, (C₉-C₃₀)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,halogen, —F, —Cl, —Br, —I, —CN, —CF₃, —N₃, —NH₂, —NHA1, —NA2A3, —NO₂,—OH, —OCF₃, —SCF₃, —SH, —O—SO₃H, —OP(O)(OH)₂, —CHO, —COOH, —C(O)NH₂,—SO₃H, —P(O)(OH)₂, —C(O)-A4, —C(O)O-A5, —C(O)NH-A6, —C(O)NA7A8, —O-A9,—O(-A10-O)_(a)—H (a=1, 2, 3, 4, 5), —O(-A11-O)_(b)-A12 (b=1, 2, 3, 4,5), —OC(O)-A13, —OC(O)—O-A14, —OC(O)—NHA15, —O—C(O)—NA16A17,—OP(O)(OA18)(OA19), —OSi(A20)(A21)(A22), —OS(O₂)-A23, —NHC(O)—NH₂,—NHC(O)-A24, —NA25C(O)-A26, —NH—C(O)—O-A27, —NH—C(O)—NH-A28,—NH—C(O)—NA29A30, —NA31-C(O)—O-A32, —NA33-C(O)—NH-A34,—NA35-C(O)—NA36A37, —NHS(O₂)-A38, —NA39S(O₂)-A40, —S-A41, —S(O)-A42,—S(O₂)-A43, —S(O₂)NH-A44, —S(O₂)NA45A46, —S(O₂)O-A47, —P(O)(OA48)(OA49),—Si(A50)(A51)(A52), —C(NH)—NH₂, —C(NA53)-NH₂, —C(NH)—NHA54,—C(NH)—NA55A56, —C(NA57)-NHA58, —C(NA59)-NA60A61, —NH—C(O)—NH—O-A62,—NH—C(O)—NA63-O-A64, —NA65-C(O)—NA66-O-A67, —N(—C(O)—NH—O-A68)₂,—N(—C(O)—NA69-O-A70)₂, —N(—C(O)—NH—O-A71)(—C(O)—NA72-O-A73), —C(S)-A74,—C(S)—O-A75, —C(S)—NH-A76, —C(S)—NA77A78, —C(O)—NH—O-A79,—C(O)—NA80-O-A81, —C(S)—NH—O-A82, —C(S)—NA83-O-A84, —C(O)—NH—NH-A85,—C(O)—NH-NA86A87, —C(O)—NA88-NA89A90, —C(S)—NH—NH-A91, —C(S)—NH-NA92A93,—C(S)—NA94-NA95A96, —C(O)—C(O)—O-A97, —C(O)—C(O)—NH₂, —C(O)—C(O)—NHA98,—C(O)—C(O)—NA99A100, —C(S)—C(O)—O-A101, —C(O)—C(S)—O-A102,—C(S)—C(S)—O-A103, —C(S)—C(O)—NH₂, —C(S)—C(O)—NHA104,—C(S)—C(O)—NA105A106, —C(S)—C(S)—NH₂, —C(S)—C(S)—NHA107,—C(S)—C(S)—NA108A109, —C(O)—C(S)—NH₂, —C(O)—C(S)—NHA110,—C(O)—C(S)—NA111A112”; wherein A1, A2, A3, A4, A5, A6, A7, A8, A9, A10,A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24,A25, A26, A27, A28, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38,A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52,A53, A54, A55, A56, A57, A58, A59, A60, A61, A62, A63, A64, A65, A66,A67, A68, A69, A70, A71, A72, A73, A74, A75, A76, A77, A78, A79, A80,A81, A82, A83, A84, A85, A86, A87, A88, A89, A90, A91, A92, A93, A94,A95, A96, A97, A98, A99, A100, A101, A102, A103, A104, A105, A106, A107,A108, A109, A110, A111, A112 are independently from each other selectedfrom the group consisting of: “alkyl, (C₉-C₃₀)alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl” and wherein alternatively A7, A8 and/orA16, A17 and/or A29, A30 and/or A36, A37 and/or A45, A46 and/or A55, A56and/or A60, A61 and/or A77, A78 and/or A86, A87 and/or A89, A90 and/orA92, A93 and/or A95, A96 and/or A99, A100 and/or A105, A106 and/or A108,A109 and/or A111, A112 respectively together can also form“heterocyclyl”; wherein optionally above substituents of substituentsgroup (i) can in turn independently from each other be substituted withone or more identical or different substituents V; n is independently 0,1, 2, 3 or 4; and the physiologically acceptable salts, derivatives,prodrugs, solvates and stereoisomers thereof, including mixtures thereofin all ratios.
 2. The compound according to formula (I) as claimed inclaim 1, wherein:

is independently substituted by a chemical group selected from the groupconsisting of:

and the physiologically acceptable salts, derivatives, prodrugs,solvates and stereoisomers thereof, including mixtures thereof in allratios.
 3. The compound according to formulae (I) as claimed in claim 1,wherein: W₁, W₂ together independently form “—N═N—, —C(O)—O—”; Y₁ isindependently selected from the group consisting of “—C(O)—,—N(R10)-C(O)—, —C(O)—N(R11)-, —OC(O)—, single bond”; Z₁ is independently“O”; B is independently selected from the group consisting of“4-chloro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl,4-trifluoromethylsulfanyl-phenyl, 4-trifluoromethoxy-phenyl,3-chloro-4-trifluoromethoxy-phenyl, 3,5-bis-trifluoromethyl-phenyl,4-isopropylphenyl, 4-tert.butyl-phenyl, 3,5-dichloro-phenyl,4-chloro-2-fluoro-phenyl, 3-chloro-phenyl,2-fluoro-5-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethyl-phenyl,3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2-methoxy-phenyl,4-methoxy-phenyl, 4-nitro-phenyl, 4-bromo-phenyl,5-chloro-2-methoxy-phenyl, 4-fluoro-phenyl, 3-bromo-4-fluoro-phenyl,6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl”; R1, R2, R3, R4, R5, R6,R7, R8, R9, R10, R11, R12, R13, R14, R15 are independently from eachother selected from the group consisting of: “hydrogen, alkyl, methyl,isopropyl, tert.butyl, halogen, —F, —Br, —Cl, —CN, —CF₃, —SF₃, —OF₃,—O-alkyl, —O-methyl, —NO₂, —S(O)₂-methyl” V is independently selectedfrom the group consisting of “hydrogen, alkyl, methyl, isopropyl,tert.butyl, halogen, —F, —Br, —Cl, —CN, —CF₃, —SF₃, —OH, —O-alkyl,—O-methyl, —NO₂, —S(O)₂-methyl”; n is independently 0, 1 or 2; and thephysiologically acceptable salts, derivatives, prodrugs, solvates andstereoisomers thereof, including mixtures thereof in all ratios.
 4. Acompound selected from the group consisting of: Compound  1

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(4- chloro-phenyl)-ureido]-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidamide Compound  2

2-[3-(4-Chloro- phenyl)-ureido]-6-(2- oxo-2,3-dihydro- benzooxazole-6-carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidamide Compound  3

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(4- trifluoromethyl-phenyl)-ureido]- 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylicacid amide Compound  4

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(4- isopropyl-phenyl)-ureido]-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidamide Compound  5

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(4- chloro-phenyl)-propionylamino]- 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylicacid amide Compound  6

2-[3-(4-Chloro- phenyl)- propionylamino]-6- (2-oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide Compound  7

2-[3-(4-Isopropyl- phenyl)-ureido]-6-(2- oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide Compound  8

2-[3-(3,5-Dichloro- phenyl)-ureido]-6-(2- oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide Compound  9

6-(1H-Benzotriazole- 5-carbonyl)-2-[2-(4- chloro-2-fluoro-phenyl)-acetylamino]- 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine-3-carboxylic acid amide Compound 10

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6-(2- oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide Compound 11

6-(1H-Benzotriazole- 5-carbonyl)-2-[2-(3- chloro-phenyl)-acetylamino]-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylicacid amide Compound 12

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(3,5- dichloro-phenyl)-ureido]-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidamide Compound 13

2-[2-(3-Chloro- phenyl)-acetylamino]- 6-(2-oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide Compound 14

2-[2-(4-Chloro- phenyl)-acetylamino]- 6-(2-oxo-2,3-dihydro-benzooxazole-6- carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3-carboxylic acid amide Compound 15

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(4- chloro-2-fluoro-phenyl)-ureido]- 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylicacid amide Compound 16

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6- pyridin-3-ylmethyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylic acid amideCompound 17

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6- pyridin-2-ylmethyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylic acid amideCompound 18

2-[3-(4-Chloro- phenyl)-ureido]-6- pyridin-2-ylmethyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylic acid amideCompound 19

2-[3-(4-Chloro- phenyl)-ureido]-6- (pyridine-3- carbonyl)-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acid amide Compound 20

2-[3-(4-Chloro- phenyl)-ureido]-6- pyridin-4-ylmethyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyiidine- 3-carboxylic acid amideCompound 21

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6- pyridin-4-ylmethyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine- 3-carboxylic acid amideCompound 22

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6-(2-pyridin-3-yl-acetyl)- 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine-3-carboxylic acid amide Compound 23

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6-(2-pyridin-4-yl-acetyl)- 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine-3-carboxylic acid amide Compound 24

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]-6-(3- pyridin-2-yl-propionyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidamide Compound 25

6-(1H-Benzotriazole- 5-carbonyl)-2-[3-(4- chloro-phenyl)-ureido]-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidmethyl ester Compound 26

2-[3-(4-Chloro- phenyl)-ureido]-6-(2- oxo-2,3-dihydro- benzooxazole-6-carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridine-3- carboxylic acidmethyl ester Compound 27

1-[6-(1H- Benzotriazole-5- carbonyl)-3- (pyrrolidine-1-carbonyl)-4,5,6,7- tetrahydro-thieno[2,3- c]pyridin-2-yl]-3-(4-chloro-phenyl)-urea Compound 28

2-[3-(4-(Chloro- phenyl)-ureido]-1H- indole-3,6- dicarboxylic acid 3-amide 6-[(2-oxo-2,3- dihydro-benzooxazol- 6-yl)-amide] Compound 29

2-[2-(4-Chloro-2- fluoro-phenyl)- acetylamino]- benzothiazole-6-carboxylic acid (2- oxo-2,3-dihydro- benzooxazol-6-yl)- amide Compound30

2-[3-(4- Trifluoromethyl- phenyl)-ureido]- benzothiazole-6- carboxylicacid (2- oxo-2,3-dihydro- benzooxazol-6-yl)- amide Compound 31

2-[3-(4-Chloro- phenyl)-ureido]- benzothiazole-6- carboxylic acid (2-oxo-2,3-dihydro- benzooxazol-6-yl)- amide Compound 32

2-[3-(4- Trifluoromethyl- phenyl)-ureido]- benzothiazole-6- carboxylicacid (1H- benzotriazol-5-yl)- amide Compound 33

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 3,5- dichloro-benzylamide Compound 34

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 4- chloro-benzylamide Compound 35

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(4- chloro-phenyl)- propyl]-amideCompound 36

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 2- fluoro-5- trifluoromethyl- benzylamideCompound 37

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2- (3,4-dichloro- phenyl)-ethyl]-amideCompound 38

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 2,5- dichloro-benzylamide Compound 39

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(4- chloro-phenyl)-ethyl]- amideCompound 40

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(4- chloro-phenyl)-1- hydroxymethyl-ethyl]-amide Compound 41

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 2- methoxy- benzylamide Compound 42

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(3- chloro-phenyl)-ethyl]- amideCompound 43

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(4- nitro-phenyl)-ethyl]- amideCompound 44

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(4- bromo-phenyl)- ethyl]-amideCompound 45

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 5- chloro-2-methoxy- benzylamide Compound46

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 4- chloro-2-fluoro- benzylamide Compound47

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid [2-(4- fluoro-phenyl)-ethyl]- amideCompound 48

[2-(1H- Benzotriazole-5- carbonyl)-1,2,3,4- tetrahydro-isoquinolin-6-yl]- carbamic acid 3,5- dichloro-benzyl ester Compound 49

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 4- trifluoromethylsulfan yl-benzylamideCompound 50

3-(1H-Benzotriazol- 5-ylcarbamoyl)- 1,4,5,7-tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 4- trifluoromethyl- benzyl ester Compound51

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 3- bromo-4-fluoro- benzylamide Compound 52

3-(1H-Benzotriazol- 5-ylcarbamoyl)- 2,4,5,7-tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 3,5- dichloro-benzyl ester Compound 53

3-(1H-Benzotriazol- 5-ylcarbamoyl)- 2,4,5,7-tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 3,5- bis-trifluoromethyl- benzyl esterCompound 54

3-(1H-Benzotriazol- 5-ylcarbamoyl)- 2,4,5,7-tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 3- chloro-4- trifluoromethyl- benzyl esterCompound 55

3-(1H-Benzotriazol- 5-ylcarbamoyl)- 2,4,5,7-tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 3- trifluoromethyl- benzyl ester Compound56

3-(1H-Benzotriazol- 5-ylcarbamoyl)- 2,4,5,7-tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 4- trifluoromethylsulfan yl-benzyl esterCompound 57

3-(1H-Benzotriazol- 5-ylcarbamoyl)- 2,4,5,7-tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 4- trifluoromethoxy- benzyl ester Compound58

3-(1H-Benzotriazol- 5-ylcarbamoyl)- 2,4,5,7-tetrahydro- pyrazolo[3,4-c]pyridine-6- carboxylic acid 3- chloro-4- trifluoromethoxy- benzylester Compound 59

(1H-Benzotriazol-5- yl)-{3-[3-(4-methoxy- phenyl)-piperidine-1-carbonyl]-2,4,5,7- tetrahydro- pyrazolo[3,4- c]pyridin-6-yl}- methanoneCompound 60

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 4- trifluoromethoxy- benzylamide Compound61

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid 4- trifluoromethyl- benzylamide Compound62

6-(1H-Benzotriazole- 5-carbonyl)-4,5,6,7- tetrahydro-2H- pyrazolo[3,4-c]pyridine-3- carboxylic acid (6- methoxy-1,2,3,4- tetrahydro-naphthalen-2-yl)- amide Compound 63

3-{[6-(1H- Benzotriazole-5- carbonyl)-4,5,6,7- tetrahydro-2H-pyrazolo[3,4- c]pyridine-3- carbonyl]-amino}-3- (4-tert-butyl-phenyl)-propionic acid methyl ester.


5. A method for inhibiting autotaxin, comprising administering to asubject in need thereof an effective amount of a compound of claim
 1. 6.Process for the preparation of a compound according to formula (I) asclaimed in claim 1, comprising the steps: (a) reacting a compound of theformula (II),

wherein W₁, W₂, R1, R2 have the meanings as indicated for the compoundof formula (I), with a compound of the formula (III)

wherein L is selected from the group consisting of:

and wherein Z₁, Y₂, R3, R4, B, n have the meanings as indicated for thecompound of formula (I), to yield a compound according to formula (I) inwhich Y₁ denotes “—C(O)—”; or (b) reacting a compound of the formula(II)

wherein W₁, W₂, R1, R2 have the meanings as indicated for the compoundof formula (I), with a compound L selected from the group consisting of:

to yield a compound of the formula (IIa)

wherein W₁, W₂, R1, R2 have the meanings as indicated for the compoundof formula (I), further reacting the compound of formula (IIa) with acompound of formula (IV)

wherein R3, R4, B, n have the meanings as indicated for the compound offormula (I), to yield a compound according to formula (I) in which Z₁denotes “O” and Y₂ denotes “—N(R16)-” and R16 denotes “H”; or (c)reacting a compound of the formula (Va) or (Vb)

wherein m and n independently are 0, 1 or 2, with a compound of theformula (III)

wherein L is selected from the group consisting of:

and wherein Z₁, Y₂, R3, R4, B, n have the meanings as indicated for thecompound of formula (I), to yield a compound according to formula (I) inwhich Y₁ denotes “—C(R12)(R13)- and R12, R13 both denote “H” or Y₁denotes “—C(O)—”, or (d) reacting a compound of the formula (VI)HO(O)C-L  (VI) wherein L is selected from the group consisting of:

with a compound of the formula (VII)

wherein W₁, W₂, R1, R2 have the meanings as indicated for the compoundof formula I, to yield a compound of the formula (VIII)

wherein W₁, W₂, R1, R2 have the meanings as indicated for the compoundof formula (I), further reacting the compound of formula (VIII) with acompound of formula (IV)

wherein R3, R4, B, n have the meanings as indicated for the compound offormula (I), to yield a compound according to formula (I) in which Y₁denotes “—N(R10)-C(O)—”, R10 denotes “H”, Z₁ denotes “O”, Y₂ denotes“—N(R16)-” and R16 denotes “H”; or (e) reacting a compound of theformula (IX)

wherein L is selected from the group consisting of:

and wherein Z₁, Y₂, R3, R4, B, n have the meanings as indicated for thecompound of formula (I), with a compound of the formula (VII)

wherein W₁, W₂, R1, R2 have the meanings as indicated for the compoundof formula (I), to yield a compound according to formula (I) in which Y₁denotes “—N(R10)-C(O)—” and R10 denotes “H”. or (f) reacting a compoundof the formula (X)

wherein W₁, W₂, R1, R2, Y₁ have the meanings as indicated for thecompound of formula (I), wherein L is selected from the group consistingof:

with a compound of formula (XI)

wherein R3, R4, B, n have the meanings as indicated for the compound offormula (I), to yield a compound according to formula (I) in which Z₁denotes “O”, Y₂ denotes “—N(R16)-” and R16 denotes “H”.
 7. (canceled) 8.A method for the treatment and/or prophylaxis of physiological and/orpathophysiological conditions, which are caused, mediated and/orpropagated by increased lysophosphatic acid levels and/or the activationof autotaxin, comprising administering to a subject in need thereof aneffective amount of a compound of claim
 1. 9. A method for the treatmentand/or prophylaxis of physiological and/or pathophysiological conditionsselected from the group consisting of: cancer, tumour, malignanttumours, benign tumours, solid tumours, sarcomas, carcinomas,hyperproliferative disorders, carcinoids, Ewing sarcomas, Kaposisarcomas, brain tumours, tumours originating from the brain and/or thenervous system and/or the meninges, gliomas, glioblastomas,neuroblastomas, stomach cancer, kidney cancer, kidney cell carcinomas,prostate cancer, prostate carcinomas, connective tissue tumours, softtissue sarcomas, pancreas tumours, liver tumours, head tumours, necktumours, laryngeal cancer, oesophageal cancer, thyroid cancer,osteosarcomas, retinoblastomas, thymoma, testicular cancer, lung cancer,lung adenocarcinoma, small cell lung carcinoma, bronchial carcinomas,breast cancer, mamma carcinomas, intestinal cancer, colorectal tumours,colon carcinomas, rectum carcinomas, gynaecological tumours, ovarytumours/ovarian tumours, uterine cancer, cervical cancer, cervixcarcinomas, cancer of body of uterus, corpus carcinomas, endometrialcarcinomas, urinary bladder cancer, urogenital tract cancer, bladdercancer, skin cancer, epithelial tumours, squamous epithelial carcinoma,basaliomas, spinaliomas, melanomas, intraocular melanomas, leukaemias,monocyte leukaemia, chronic leukaemias, chronic myelotic leukaemia,chronic lymphatic leukemia, acute leukaemias, acute myelotic leukaemia,acute lymphatic leukemia, lymphomas, angiogenesis, arteriosclerosis,opthalmic diseases, choroidal neovascularization, diabetic retinopathy,inflammatory diseases, arthritis, neurodegeneration, restenosis, woundhealing and/or transplant rejection, comprising administering to asubject in need thereof an effective amount of a compound of claim 1.10. (canceled)
 11. (canceled)
 12. A pharmaceutical compositioncomprising a compound as claimed in claim 1, and a pharmaceuticallyacceptable carrier.
 13. The pharmaceutical composition as claimed inclaim 12 further comprising at least one additional pharmaceuticallyactive substance other than the compound of formula (I).
 14. A kitcomprising a compound as claimed in claim 1 and furtherpharmacologically active substance other than the compound of formula(I).